ISSN:0069-3030    

DOI:10.1039/OC99390FX001

出版商:RSC    

年代:1993

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC99390BX003

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

CTIONARY OF SUBSTANCES AND THEIR EFFECTS Dictionary of Substances and their Effects (DOSE) is a new unique user-friendly guide to 5,000 chemicals and the impact they have on life forms and the environment across the globe. Compiled with the aid of official lists from the EC UK USA and Canada DOSE comes in seven alphabetical volumes each containing an index of chemical names CAS registry numbers and molecular formulae as well as a glossary of biological organisms. A separate volume containing cumulative indices of all volumes is also available. DOSE LISTS EACH CHEMICAL'S 0 IDENTIFIERS 0 USES 0 OCCUPATiONAL EXPOSURE 0 ECOTOXICITY 0 STATUS IN LEGISLATION WORLDWIDE 0 MAMMALIAN TOXICITY 0 EFFECTS ON SEWERAGE WORKS PROCESSES 0 PHYSICAL PROPERTIES DOSE enables the user to make rapid hazard assessments of chemicals facilitating risk assessment and further action.Such a store of information is of critical importance to scientists environmentalists industry professionals regulators and researchers -indeed anyone affected by or concerned about chemicals and their potential effects on the environment the world over. ORDER TODAY FOR THE FUU RECORD OF CHEMICAL EFFECTS DOSE Prices All volumes hardcover Volume 3 Da-Dim) Volume 4 [Din-H)Volume 5 I-M) Volume 7 (S-2)Volume 6 IN-R) Complete Set 951 pages 876 pages 760 pages 998 pages c.900 pages 975 pages c.900 pages ISBN 0 85186 331 0 ISBN 0 85186 341 8 ISBN 0 85186 351 5 ISBN 0 85186 361 2 ISBN 0 851 86 371 X ISBN 0 85186 340 X ISBN 0 85186 330 2 ISBN 0 85186 381 7 1992 119931 1993 119941 Price f180.00 Price €180.00 Price €180.00 Price f180.00 Price f1500.00 ThemIs no members' dlemvnt forthlrproduct To order pl~se contact The Royal Societyof Chemist Turpin Distribution SewicesLimited,Blackhone Road THE ROYAL Letchworlh,HertsSG6 1HN.l%ited Kingdom. Tel +44(0)1462 672555. Fax +44 (0)1462480947. SOCIETY OF RSCmemkrr ordering for pemorui use are entitled to a discount on most RSC product. and should contact Membership Administration Department The Ro al Socie ofChemistry Thomas GrahamHouse Science Park. Milton Road Cambridge CB4 4Wt Unitedft;ng$m Tel +44 (0)1223 420066. Fax:+44 1011223 423623. E-mail [internet):RSCI ORSC.OR .. .. Information For further infmatlon on RSC producu please Contact the %lea and PromotionDepartmentat our Services C8mbridge address.Rd No 975 Thin Film Coating Edited by H. Benkreira The Univem'ty of8radfd Thin Film Coating reviews imptant new work in the fluid mechanics of coating flows(pcediction and correlation of film thickness and quality with operatin conditions) the rheology of coati suspensions (and its effect on coating performance) drying and solvent recovery in coating processes.% is written by world experts in eTeld and gives an update on the many advances mack in the subject both in academic research and in industrial development. The im ltance of coatin technology is well known yet it remains a fra mted field where a varie of coatin methods and approaches haw &n created to wfve operational problems. 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ISSN:0069-3030    

DOI:10.1039/OC99390BP015

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

2 Physical Methods and Techniques Part (ii) Mass Spectrometry By C. P. BALL and P.J. DERRICK Department of Chemistry University of Warwick Coventfy CV4 7AL UK 1 Introduction Mass spectrometry (MS)is currently enjoying a period of rapid expansion due in large part to the developments in methods of creating gaseous ions from complex molecules and molecular assemblies. Applications of mass spectrometry in structural biochemis- try are attracting a great deal of attention in particular those made possible by the advances with electrospray and Fourier transform ion cyclotron resonance (FT-ICR). The possibilities of studying non-covalent interactions between proteins and substrates are widely discussed and there have been examples of such interactions apparently surviving intact the transition from solution to vacuum (vide infra).Matrix-assisted laser desorption/ionization (MALDI)Is of great current interest and there is again an exciting possibility that through MALDI mass spectrometry will come to make significant contributions in the field of polymer science. On the more physical side of the subject the advances are in the sophistication of experiments to study the behaviour of gaseous ions. The complexity of the systems which can be studied increases steadily and the level of detail provided by spectroscopic and ion-molecule experiments steadiiy rises. Meanwhile gas-phase ion chemistry has truly come of age and knowledge from mass spectrometry on organic mechanisms and metal-organic interactions does now have relevance far beyond the bounds of mass spectrometry.2 Physical Organic Chemistry Mass spectrometry remains a wideiy-used method for the elucidation of organic reaction mechanisms particularly if short-lived intermediates are involved. Increasing- ly isotopically labelled compounds are studied nut simply to ‘tag’ particular atoms in an ion but so as to make use of kinetic isotope effects to elucidate reaction mechanism.’ Distonic ions and ion-molecule complexes have become more firmly established as important concepts in gas-phase ion chemistry over the last two years. ZeIler et a1.2 have found that long-lived radical cations of simple organophosphate esters isornerize spontaneously to more stable distonic structures in the gas phase. On the basis of cullision-induced dissociation experiments Bowen and Wright3 proposed that the P.C.Burgers C.A. Kingsmilf G.A. McGibbon and J. K. Terlouw Org. Mass. Spectrom. 1992,27 398. L. Zeller J. Fartell Jr. H.I. Kenttamaa and P. Vainiotalo J. Am. Chem. SOC.,1992 114 1205. R.D. Bowen and A. D. Wright J. Chem. Soc. Chem. Commun. 1992 96. 21 C. P. Ball and P. J. Derrick crucial step in alkyl radical loss from ionized pentenyl and hexenyl methyl esters involves a 1,Zhydrogen shift at the radical site of a distonic ion followed by y-cleavage of the resultant ionized enoI ether. The loss of water from ionized ethyl furmate produced4 the rarely seen ion -CH,CH,CO+. The distonic ion *CH,OSi* was shown to be stable by Srinivas et ~l.,~ the ions being generated by electron-impact ionization of Si(OCH,),.Holmes and coworkers" have shown that intramolecular hydrogen bonds in /?-diols and b-hydroxy ethers are not preserved in their molecular ions. The fragment ions of metastable formyl loss from ionized ethylene glycol and 2-methoxyethanol have been shown to be the conjugate acids of methanol and dimethyl ether re~pectively.~ Mechanisms involving ion-neutral complexes were ruled out and it was concluded that distonic ions were the intermediates. A new isomer of dimethyl propyl phosphate was synthesized by transfer of ionized ethylene to trimethylphos- phate in the gas phase,* and it was proposed that this ion has separate radical and charge sites. The distonic radical cation CSH5N'-C'CH2 has been generated by reacting pyridine with the radical cations of cyclopropane ethylene oxide and ketene.This species transfers (CH,)" to more nucleophilic substituted pyridine~.~ The 8-distonic ion formed by the reaction between pyridine radical cation and ethene behaves differently. It can Iose C,H by coIlisionaI activation or can ionize again giving a doubly-charged ion. This 8-distonic ion requires collisional stabilization to be visible. The ortho effects in collision-induced dissociation of closed-shell aromatic ions has been examined using both quadrupole ion traps and triple quadrupole mass spectrometers.' The meta and para isomers were found to have qualitatively similar dissociation pathways whereas the ortho isomers dissociated differently.Several isomers of C,H,O+ and C,H,S * ions were distinguished using ion-molecule reactions with isoprene and methylanisoks to show that the ions have different reactivities depending on the precursor molecule from which they are generated. l2 Epimers of methylcyclohexanol were distinguished on the basis of their relative gas-phase acidities which were obtained using a kinetic method based on the relative rates of competitive fragmentation of cluster ions.' McCarley and Brodbelt have studied the behaviour of 174-benzodiazepinsin ion-molecule reactions using a quadrupole ion trap. The reactions with dimethyl ether ions give selectively formed adducts which can be used to diagnose the benzodiazepin ~tructure.'~ Huang and Dunbar" studied the breakdown pattern of n-heptane ions by photodissociation and discovered that the m/z 71 and 43 ionabundanceswere strongly dependent upon the internal energy of the parent ion.Photodissociation and photoionization techniques have been employed very successfully to elucidate not only C.E. Hudson and D.J. McAdoo Org. Mass. Spectrom. 1992,27 1384. R. Srinivas D. K. Bohme 1. Hrusak D. Schroeder and H. Schwarz J. Am. Chem. Soc. 1992,114,1939. J. R.Cao,M.Georgqf. L. Holmes M. Sirios,J. K.Terlouw and P.C. Rurgers,J. Am. Chem.Soc. 1992,114 2017. ' H.E. Audier A. Milliet D. Leblanc and T.H. Morton J. Am. Chem. Soc. 1992 114 2020. L.K. M. Kiminkinen K. G. Stirk arkdH.I. Kenttamaa J. Am. Chem. Soc. 192,114 2027. S.J.Yu and M.L. Gross @rg.Mass. Spectrom. 1993,4 117.S.J.Yu C.L. Holliman D. L. Rempel and M.L. Gross J. Am. Chem. SOC. 1993 115 9676. T. Donovan and J. Brodbelt Org. Mass. Spectrom. 1992 27,9. l2 M.N. Eberlin T.K. Majumdar and R.G. Cooks,J. Am. Chem. SOC. 1992,114,2884. l3 T. K. Majumdar F. Clairet J.C. Tabet and R.G. Cooks J. Am. Chem. Soc. 1992 114,2897. l4 T. D. McCarley and J. Brodbelt Ad. Chem. 1993,65,2380. S.F. Huang and R.C. Dunbar Int. J. Mass Spectrom. Ion. Processes 1992 112 101. Physical Methods and Techniques -Part (ii) Mass Spectrornefry 23 fragmentations of ions but also of neutrals such as alkenes and dienes.'6-17 Energy randomization in the benzene dimer ion has been studied by Boernson and Se1zle.l' Employing isotopically mixed benzene dimers it was demonstrated that charge and energy can be totally shared.At higher energies fragmentation can however occur without communication between the two dimer halves. The kinetic energy releases of the photodissociation processes C,H,SH + hv (193nm) +C,H + SH and C,H,SCH + hv (193nm) +C,H + SCH and C,H,S + CH were measured by a time-of-flight mass spectrometric method; values for the dissociation energies of the C,H,-SH C,H,-SCH, and C,H,S-CH bonds at 0 K were obtained.'' The boryliurn ions (CH,OBOCH,)+ and (CH,BCH,)+ studied by dual-cell FT-ICR showed an unusual bimolecular reaction involving the facile abstraction of a water molecule from an organic ether." Ruscic and Berkowitz have studied the products of the reactions of fluorineatoms with MeSH by photoionization mass spectrometry.They found adiabatic thresholds at m/z 47 of 7.536 f0.003 eV and 9.262 f 0.005eV identified as the adiabatic ionization energies of CH,SH and MeS respectiveIym2 Gable Phan and Griffin have generated the iodiranium ion by gas-phase reaction of ethylene with positive ions generated from The unimolecular chemistry of methyl formate cation radical has been studied by Heinrich et aLZ3 The mobility of t-butyl ion within t-butyI substituted diphenylalkanes has been investigated by Kuck and Matthia~.*~ Metastable protonated 4-Bu'C,H4CH,Ph lost isobutane following the abstractionof a hydride by the t-butyl ion from the benzylic C-H bonds in a n compkx. Protonated 4-Bu'C,H,(CH2),Ph did not involve free t-butyl ions but did involve an ion-neutral complex.McGibbon et aL2' have determined stabilization energies of a-and fl-silyI substituents of vinyl cations by measuring the appearance energm for metastable peaks for loss of I' from Me,SiCI=CH and (E)-Me,SiCH=CHI. Enantioselectivity in fast atom bombardment (FAB) MS was established by using a complex of a selected aldohexose derivative with an enantiomeric pair of naphthyl ether ammonium ions.' The selectivity was detected and evaluated from the relative intensities of the 1 :I adduct ions (formed with an internal standard of 12-crown-4). Similar results were seen using a crown ether host with an ammonium ion guest. It has been claimed that the absolute configurations of a sample molecule can be predicted by examination ofthe FAB mass spectra of the sample measured with reagents of R and S c~nfiguration.'~ The proton affinities of 21 amines have been calculated using data from collision experiments using a hybrid tandem mass spectrometer.These results can be used to estimate the proton affinities of amino acids aside from those containing a l6 S.E.Van Bramer and M.V.Johnston,Org. Mass. Spectrom. 1992,27,949. l7 S. E. Van Bramer P. L,Ross and M. V. Johnston J. Am. SOC.Mass Spectrom. 1993 4,65. K.0.Boernsen and H. L. Selzle Chem. Phys. Lett. 1992,190,497. I9 S. Nourbakhsh H. M. Yin,C. L. Liao and C.Y. Ng Chem. Pltys. Letr. 1992 190,449. T. D. Ranatunga and H.I. Kenttamaa 1.Am. Chem. Soc. 1992 114,8600. B. Ruscic and J. Berkowitz J. Cltem. Phys. 1992.97 1818. 22 K.P.Gable T.N.Phan and D. Griffin Org. Mass.Spectrom. 1993 28 397. 23 N. Heinrich T. Drewello P.C. Burgers J. C. Morrow 3. Schmidt W. Kulik J.K. Terlouw and H. Schwarz J. Am. Chem. Soc. 1992,114 3776. *' D. Kuck and C. Matthias J. Am. Chem. Soc. 1992 114 1901. 25 G.A. McGibbon M. A. Brook and J. K. Terlouw J. Chem. SOC.,Chem. Commun. 1992 360. z6 M. Sawada M. Shizuma Y. Takai H. Yamada T. Kaneda and T,Hanafusa J. Am. Chem. Soc. 1992,114 w5. " H. Yang and Y. Chen Org. Mass. Spectrom. 1992 27 736. 24 C. P. Ball and P. J. Derrick functional group capable of stabilizing a protonated species by hydrogen bonding.28 The question of whether the McLafferty rearrangement of ketones is concerted or stepwise has been addressed by Bowie Derrick and coworkers,29 using intramolecular I3Cand 2Heffects They conclude that the isotope effects observed are consistent with a stepwise mechanism with more than one rate-determining step.Ionized 4-rnethoxyheptane exhibits just two significant fragmentations which consist of hydrogen transfer steps with interesting site ~electivity.~' Ketene has been discovered to dirnerize in the gas phase when ionized by low-energy charge exchange.31 Morton has addressed the reorientation criterion with regards to positive ion-neutral Ion-neutral complexes have been convincingly invoked in quite a number of mechanistic st~dies.~~~'~ Morton postulates two categories of gaseous ion-neutral complexes potential energy barriers prevent the separation and collapse oftype 1 complexes but only an entropic barrier prevents the collapse of a type 2 complex.Isotopic labelling has shown that the dissociation of the metastabk ion AcCH2CO+ to produce the Ac' ion is preceded by an atom exchange involving an ion-neutral ~ornplex.'~ An ion-neutral complex intermediate has been postulated for the loss of water from fatty acid carboxyhtes by Jensen Haas and Gross.36Fatty acid carboxylates formed by FAB have been found to undergo both metastable ion and collisionally activated dissociation (CAD) to eliminate water. Upon CAD the water elimination competes with charge-remote fragmentation and deuterium labelling suggested that the elimination proceeds uia an ion-neutral complex. Mass-analysed ion kinetic energy spectroscopy (MIKES) has been used to examine the unimolecular reactivity of the protonated forms of EtCN and EtNC in the gas phase.Both species were found to isomerize into weak n complexes between ethene arid CH=NH +,which may then dissociate or interconvert. The 1,2 elimination processes proposed may require the intermediacy of loosely bound ion-neutral [M -HI -ions prepared from 17#?-oestradiol- 17 fatty acid esters by negative-ion chemical ionization have exhibited interesting low collisional energy processes.38 Both phenoxide and enolate forms of the [M -HI-were seen. Evidence was produced for molecular isomerizations into iondipole complexes. The mechanism of [IH,C,N]loss from metastable molecular ions of benzene cyanides containing F CI CF, CH, OH or CH,O substituents has been investigated by deuterium and I3C labelling.39 The eliminations from the F Cl or CF,-substituted species was found to involve a randomization of the hydrogen atoms and a minor rearrangement of the CH,CN function causing expulsion of a benzylic carbon 2&30% of the time.When the substituents are CH, OH or CH30 there appears to 28 X. Li and A.G. Harrison Org. Mass. Spectrom. 1993 28,366. 29 M. B.Stringer D. J. Underwood J.H. Bowie C. E. AJIison K. F. Donchi and P.J. Derrick Org. Mass. Spectrom. 1992 27 270. 30 R.D. Bowen and P. J. Derrick 1.Chem. Soc. Perkin Trans. 2 1992 1041. 31 C.H. Dass Rapid Commun. Mass Spectrom. 1993 7 95. 32 T.H. Morton Org. Mass. Spectrom. 1992 27 353. 33 V. Nguyen X. Cheng and T.H. Morton J. Am. Chem. SOC.,1992 114 7127. 34 M. Gu and F. Turecek J. Am. Chem.SOC.,1992 114 7146. 35 J. Tortajorda D. Berthomieu J. P. Mariztlr and H. E. Audier 1.Am. Chem. Soc. 1992 114 10874. 36 N. J. Jensen (3.W. Haas and M. L. Gross Org. Mass. Spectiom. 1992 27 423. 37 G. Bouchoux,M.T. Nguyen and P. Longvialle J. Am. Chem. Soc. 1992 114 1OOOO. 38 L. Debrauwer A. Paris D. Rao F. Fournier and J.C. Tabet Urg. Mass. Spectrum. 1992 27 709. 39 T. A. Molenaar-Langeveld R. H. Fokkens S. Ingemann and N. M. M. Nibbering Org. Moss. Spectrorn. 1992 21 390. Physical Methods and Techniques-Part (ii) Mass Spectrometry 25 be a rearrangement of the meta and para isomers to the ortho isomers. Tkaczyk and Harrison have deveIoped a method for the identification of esters by colIisiona1 charge inversion of their enolate ions.4o The enolate ions of m/z 115 derived from the four butyl acetates have been distinguished by their coilisional charge inversion and neutraliz- ation-reionization mass spectra.The reactions of the ion HC,=CHCH=U+CH, generated by radical loss from allylic alkenyl methyl ethers have been probed using 2H and 13C labelling experirnent~.~’ 3 Fulkrenes and Clusters Mass spectrometry has always had a connection with the field of fullerenes and these compounds have continued to generate a huge amount of intere~t.~’ Gaseous C, was studied by photoionization mass spectrometry between the ionization threshold and 40.8eV.43 Fragmentation to form C;8 was only observed at the highest energy and Ci; also became more prominent with increasing energy. An adiabatic threshold of 7.57 20.01 eV was observed for C&,.An Fe adduct with C, was obtained by carrying out contact-arc vaporization of graphite in a partial atmosphere of [Fe(CO)6].44 The properties of the molecule differ from those of a moIecule prepared with Fe outside the cage by solution methods.Wu,Christian and Anderson examined the effects of colliding a beam of Ne’ with C, vapo~r.~’ (26 has been found to add to a large variety of neutral and charged n~cleophiles,4~ and to exhibit fade reactivity with CH in both positive and negative ionization. The reaction of fullerenes with fluorine gives a variety of products which may well have the fluorine externally attached to the ~keleton.~’ C, and C, in 3-nitrobenzyl alcohol and 2-nitrophenyl octyl ether have been investigated by both positive and negative-ion FAB.48 Many protonated and hydroxylated ions were observed.Collision-induced dissociation of the fuIlerene- adduct ions indicated that the oxygen and hydroxyl were connected to the outer surface of the fullerene. A four-sector tandem mass spectrometer was used to prove that as a result of collisions small target gases such as helium and deuterium are incorporated into intact fullerene radical cati~ns?~ The internal energy of these complexes was varied by changing the centre-of-mass coIlision energy which is converted into the internal energy of the complex when the target gas is captured. The formation of endohedral (C6,He) + complexes in mass spectrometric experiments has been modelled with molecuIar dynamic sir nu la ti on^.^^^ These simulations predicted optimal complex formation at a C& incident energy of 8000eV.The results were consistent 40 M. Tkaczyk and A.G. Harrison Org. Mass. Spectrom. 1992 27 585. *’ R. D. Bowen A. W. Colburn and P.J. Derrick Org. Mass. Spectrom. 1992 27 625. *’ S. W. McElvany and M. M. Ross,J. Am. Soc. Mass Spectrom. 1992 3 268. *’ R.K. Yoo,B. Ruscic and J. Berkowitz J. Chem. Phys. 1992 % 911. 44 T. Pradeep,G. U. Kulkarrti K. R. Kannan T. N. Row and C. N. R. Rao J. Am. Chem.Soc. 1992,114,2272. *’ Z. Wu J. F. Christian and S. L. Anderson J. Chem. Phys. 1992 % 3344. 46 F. Wudl A. Hirscb K. C. Khemani,T. Suzuki P. M. Allemand A. Koch H. Eckert G. Srdanov and H. M. Webb in ‘Fullerenes’ ACS Symposium Series no. 481 ACS Washington DC 1992 p.161. *’ K. Kniaz J.E. Fischer H. Selig G. B. Vaughan W. J. Romanow D. M. Cox S. K. Chowdhury J. P. McCauley R.M. Strongin and A. 3. Smith 111 J. Am. Chem. SOC. 1993 115,6040. 48 J. M. Miller and L. 2. Chen Rapid Commun.Mass Spectrom. 1993,6 184. *9 K. A. CaIdweIl D.E. Giblin and M. L. Gross J. Am. Chem. Soc. 1992 114 3743. S. W. McElvaney M. M. Ross,and J.H. CalIahan Ace. Chem. Res. 1992 % 3344. ” R.C. Mowrey M. M. Ross and J.H. Callahan J. Phys. Chem. 1992,% 4755. 26 C. P. Ball and P. J. Derrick with a collision involving momentum transfer between He and an isolated portion of Czo.Lykke and Wurtz have reported neutral products from photodissociated C, for the first time.s2 The electron impact cross section of Ce0was determined by Baba and coworkers5’ using Knudsen cell mass spectrometric techniques to be (5.35 4 5.5) x 10-16m2at 38 eV.Doubly-charged negative ions of fullerenes have been produced by chemical ionization using isobutane as the reagent gas. The efficiency of the attachment increases with the size of the fullerene. Under Iow-energy collision conditions an electron is ejected54 from the doubly-charged C:; ion to form C;:. Knudsen cell mass spectrometry of pure C6* was carried out at 600-800K to determine5’ the vapour pressure and sublimation energies of C,o. Evidence of a ‘radical sponge’ effect of C, has been presented by McEwen McKay and Larsen when additions of H CH, and C,H to C6* were observed using methane as the source under electron attachment conditions.s6 The results are explained by a mechanism in which radicals produced in the gas phase react with c6 at a surface.Multiphoton ionization of fullerenes has shown prompt electrons resulting from direct two-photon ionization as well as a low-energy delayed electron signal following a thermal energy distribution with average energy of E-= 0.3 & 0.05 eV. The results lead to an estimate5’ of the photoionization cruss-section for C, in the lowest triplet state of (5.1 2.0) x 10-17~-2. Delayed ionization of fullerene over a timescale of 15 ps was reported in good agreement with Klots’ model for thermionic emission.58 FAB of fullerenes using helium argon or xenon beams gives characteristic patterns with helium showing abundant triply-charged peaks.” Soluble yttriurn-containing metallofullerenes YC, and Y2c82 were obtained from yttrium-carbon soot and detected using laser desorption time-of-flight (TOF)mass spectrometry which showed a series of peaks Y,C2 (2n = 84,905 2n 5 The metallofullerenesYC, and YC,o were not observed.The Yc82 compound was shown by X-ray crystallography to have a Y-Y interacton with the Y-Y neighbour distance at 4.05 0.05 A,61which might indicate that Y is not endohedral. Gas-phase Y-fullerene adduct ions (Y,C,)* (x = 1,2) with even numbered n of 60-100 were formed in a FT-ICR mass spectrometer by direct laser ionization of graphite and Y20 These compounds were found to be extremely stable towards fragmentation and oxidation and hence it was proposed that they could be endohedral.Endohedral scandium fullerenes have been produced by arc burning scandium oxide/carbon graphite rods.6 The fullerenes were confirmed as discandium fullerenes by MALDI ” K.R.Lykke and P. Wurtz J. Phys. Chem. 1992,% 3191. ” M.Sai. Baba T.S. L. Narasimhan R. Balasubramanian and C.K. Mathews Int. J. Mass Spectrom. Ion. Processes 1992 114 R1. ” A. Mandelbaum and A. Etinger Org. Mass.Spectrom. 1993 28 487. ” C. K. Mathews M. S. Baba,T. S. L. Narasimhan R.Balasubramanian,N. Sivaraman,T. G. Srinivasan,and P. R.V. Rao J. Chem. Phys. 1992,% 3565. s6 C. N. McEwen R.G. McKay and B. S. Larsen J. Am. Chem. Suc. 1992 114,4412. 57 D. Ding R.N. Compton R. E. Haufler and C. E. Klots J. Phys. Chem. 1993,97,2500. ’’ E. E. B. Campbell G. Ulmer and I.V. Hertel Z. Phys.D:At. Mol. Clrrsrers 1992 24 81. 59 M. Takayama and H. Shinohara Inr. J. Mass Spectrom. Ion Processes 1993 123,R7. 6o H. Shinohara H. Sato Y. Saito M. Ohkohchi and Y. Ando J. Phys. Chem. 1992 % 3571. 61 L. Sonderholm P. Wurz,K. R. Lykke D. H. Parker and F. W. Lytle J. Phys. Chem. 1992 % 7153. S.W. McElvany J Pbys. Chem. 1992 % 4935. 63 H. Shinohara H. Yamaguchi N. Hayashi H. Sato M. Obkohchi Y. Ando and Y. Saito J. Phys. Chem. 1993,97,4259. Physical Methods and Techniques -Part (ii) Mass Spectrometry 27 and have the formulae SC~@C~~ sc,@c8, and sc,@C,,. Propane(1 + bpropane [(C,H~)(C,H,),,] cluster ions induced by isornerization of the propyl ion have been observed by Foltin et a1.64to decay by the evaporation of up to four propane monomers as well as the normal single-monomer evaporation.This additional fragmentation is described by a new decay mechanism. Dissociative ionization of clusters has been studied using photoionization by vacuum UV laser dispersed light from synchrotron sources or discharge light SOUTCXP 4 Organometallics Mass spectrometry is being used increasingly to study reactions of metal ions with organic molecules. A review has been written by Teesch and A review has appeared comparing the primary processes undergone by transition metal complexes in photochemical excitation in solution and FAB in a matrix.67 Schroeder et d.have studied the gas-phase oxidation of methane by FeO . There + was evidence68 of four distinguishable isomers of [Fe,C,H,,O] . Fisher and Atmen-+ trout"g investigated the activation of alkanes by Cr +,employing ion-beam mass spectrometry to study the reactions of ground-state Cr' (6S) with propane butane methylpropane dimethylpropane and selectively deuteriated propane and methyl- propane.Ground state Cr+ ions were found to undergo no bimolecular reactions at therrna1 energies but did react at elevated kinetic energies. The structure and mechanisms of formation of (C,H,Fe)+ produced by electron impact on q-C,H,Fe(CO),CH were examined by Uggerud and coworkers7' using collisional activation. The ions consist of a 1 1 mixture of benzene-iron and fuhene-iron structures and two different fragmentation pathways were observed. Fe' was shown to mediate in [4 + 21 additions of buta-1,3-diene with ethyne and propyne.The proposed mechanisms involve formation of [Fe(benzene)f'for the ethyne reaction and [Fe(toIuene)] for the reaction with propyne. [FeCp] was generated at low pressure and its sequential reactions with ethylene oxide and related heterocycles monitored. Molecular mass determination of ferrocenyl-aryl-plumbanes has been carried out by californium-252 plasma desorption combined with TOF analysis.72 Positive and negative plasma desorption mass spectra of methylbenzenethiol cadmium salts which are three-dimensional non-molecular materials were found to contain fragment ions directly related to the compound lattice struct~re.'~ A reverse-geometry tandem mass spectrometer was used to analyse the unimolecular and collision-induced dissociation of doubly-charged porphyrins containing nickel and vanadyl ions.The major reactions were classified and illustrated with appropriate 64 M. Foltin V. Grill T. Rauth Z. Herman and T. D. Maerk Phys. Reo. Lert. 1992,68 2019-22. 65 J.A. Booze and T. Baer J. CAem. Phys. 1992,% 5541. "L. M.Teesch and J. Adams Org. Muss.Spectrom. 1992 27 931. '' T.J. Kemp Coord. Ckem. Rev. 1993 125 333. D. Schroeder,A. Fieidler J. Hrusak and H. Schwarz J. Am. Chem. SOC. 1992 114 1215. 69 E. R. Fisher and P.B. Armentrout J. Am. Chem. Soc. 1992 114 2039. 'O D. Ekeberg G. Hvistendahl Y. Stenstroem and E. Uggerud Actu Chem. Scund. 1992 46,92. 'I R. Bahktiar J.J. Drader and D. B. Jacobson J. Am. Ckem. SOL 1992 114,8304. l2 G. Ailmaier 0.Roepstroff and K. E. Schwarzhans Rapid Commun.Mass Spectrom. 1992 6 58. l3 A.G. Craig D. Kinny R. Garbutt 1.G.Dance and P. J. Derrick Org. Mass.Spectrom. 1992 27 1019. 28 C. P. Ball and P. J. Derrick spectra and information from tandem quadruple experiments was presented.74 Electrospray(ES) and four-sector tandem mass spectrometry has been used to study complexes of lanthanides and trifl~oracetylcamphorates.~Electrospray mass spectra of mercury phosphine complexes has been used to examine the cation exchange that readiIy takes place with these species.76 5 Polymers Developments in electrospray and more particularly MALDI are revolutionizing the mass spectrometry of polymers. Mass discrimination has been reported however in the laser desorption-FT-ICR mass spectrometry cation-attachment spectra of poly-mer~.~~ It is unclear whether mass discrimination occurs with laser desorption and FT-ICR of polymers in general.The interactions by collision-induced decomposition and ion-molecule reactions of poly(ethy1ene glycol) and ethoxylated alcohols have been studied by FT-1CR. PoIy(ethy1ene glycol) when protonated can transfer protons to both polymer and alcohol and measurements of the proton affinity and entropy of protonation of the ethoxylated alcohols give evidence for a strong intramolecular hydrogen bond.78 Plasma desorption mass spectrometry has become less popular in recent years but work is still being carried out using this technique on polymers. Coincidence-counting techniques were used with TOF mass spectrometry to study the impact of MeV/amu ions on surfaces.79 Correlations were observed between proton emission and certain hydrocarbon-ion emissions from polymer samples. 252Cf fragments were used to probe the surface of polystyrene/PVME blends by coincidence-counting TOF mass spec- trometry.8o Nohmi and Fenn have shown that ions formed from electrosprayed poly(ethy1ene oxide) with molecular weights from 200 to 5ooOOOO can be mass ana1yseds8' The number of charges per unit length decreased with increasing molecular weight for molecular weight below 2OOOO. Above this figure the number of charges per unit length increased. Above 5 OOOOOO the number exceeds that allowed by the electrostatic model. Two different mechanisms were proposed for formation of ions from charged droplets.MALDI-TOF has been used to examine the absolute masses and mass distribution of poly(styrene sulfonic acid) and poly(acry1ic acid).*' MALDI was used successfully to characterize polyethylenes PMMA polystyrene and poly(ethy1ene glycols) by the use of appropriate matrices and the addition of metal salts. Molecular masses up to 70000Da are observed but no fragmentati~n.'~ It has also been discovered that A1+ Cr+ Fe' and Cu' all attach efficiently to polystyrene and poIy(ethy1ene glycol) in 74 G.J. Van Berkel S. A. Mctuckey and G. L.Glish J. Am. SOC.Mass Spectrom. 1992,3,235. 75 J. M.Curtis P.J. Derrick A. Schnell E. Constantin R.T. Gallagher and J. R. Chapman Org. Mass. Spectrom. 1992 27 1176. '' R. Colton and D. Dakternieks Inorg.Chim. Acra 1993,208,173. 77 J.D. Hogan and D.A. Laude Jr. Anal. Chem. 1992,64 763. '* H.Y. Lin,A. Rockwood M. S. B. Munson and D.P. Ridge Anal. Chem. 1993,65 2119. 79 M.A. Park E.A. Schweikert and E. F. Da Silveira J. Chem. Phys. 1%2,% 3206. '' D. B. Cox M. A. Park G.R. Kaercher and E.A. Schweikert Anal. Chem. 1992,64,843. T. Nohmi and J.B. Fenn J. Am. Chem. SOC. 1992,114 3241. *' P. 0.Dank D. E. Karr F. Mayer A. Holle and C.H. Watson Org. Mass. Spectrom. 1992,27,843. 83 U.€3ahr A. Deppe M.Karas and F. Hillenkamp Anal. Chem. 1992,64,2866. Physical Methods and Techniques -Part (ii) Mass Spectrometry 29 laser desorption TOF mass Spectrometry. The metals can be added either by applying the salt to the matrix or by desorption from a metal support.84 6 Bioorganic Compounds Using ES mass spectrometry it has been possible to demonstrate the attachment of coenzymeA to a flavodoxin by a modified strain of Escherichia coli.8sIon-spray mass spectrometry has been used to characterize lipopeptides with high sensitivity and simple sample preparati~n.~~ Molecular mass determination up to 6000 Da with an accuracy of I Da was routinely possible.Using 266 nm laser desorption foIlowed by 255 nm multiphoton ionization a variety of structurally significant sequence fragment ions have been obtained for pep tide^.'^ The fragment ions were mostly obtained during the 266 nm Iaser desorption. A variety of immoniurn ions were also formed at higher ionizing power densities which gave an overview of the amino acid residues present.Fragment ions observed in mass spectra produced during resonant 266 nm laser desorption may originate as neutral fragments formed from the intact molecule during laser desorption and subsequently post- ionized.'' MALDI-TOF and ES ionization were used to investigate the interactions of copper@)ions with a 26-residue sequence of amino acids found on the surface of the human plasma metal-transport protein histidine-rich gIycoprotein.89 The peptide (GHHPH),G was reacted with copper and manganese and was observed to bind one copper ion per repeat unit. Manganese showed no reaction. New reagents are frequently proposed for the Edrnann degradation and one such has been heavily studied by mass spectrometric methods." 3-[4'-(ethylene-N,N,N-trimethylamino)phenyl]-2-isothiocyanatewas detected as amino acid derivatives with high sensitivity by ion-evaporation mass spectrometry.Sensitivity was subferntomolar and amino acids of all types of side chain were detected with equal facility. The polar nature of the reagent required covalent immobilization of polypeptides prior to automatic sequence analysis. The veterinary drugs dimetridazole and ipronidazole and their metabolites were detected in turkey muscle by HPLC followed by thermospray tandem mass spec- trornetryg' at the ppb Ievel. Tandem mass spectrometry confirmed the identity of the drugs and their metabolites. TaxolQ cephalornannine and baccatin HI@ have been detected by tandem mass spectrometry in crude plant extracts at less than 500pg q~antities.~~ No interferences were observed.Diciofenac@ an antiinflammatory drug has been investigated by means of electron impact chemical ionization and FAB tandem mass spectrometry along with hydroxylated metabolite^.^^ GC-MS with C. F. Llenes and R. M. OMalley Rapid Commun. Mass Spectrom. 1992 6 564. " R. N. F. Thorneley C. Abell G. A. Ashby M. H. Drurnmond R.R.Eady S. Huff C.J. Macdonald and A. Schneier Biochemistry 1992 31 1216. 86 J.W. Metzger W. Beck and G. Jung Angew. Chem. 1992 104 235. '' G. R. Kind 3. Lindner and J. Grotemeyer 1.Chem. Phys. 1992 96 3157. 88 G. R. Kinsel 1. Lindner and J. Grotemeyer J. Chem. Phys. 1992 96,3162. 89 W.T. Hutchens R. W. Nelson,M.H. Allen C. M. Li and T.T. Yip Biol. Mass Spectrom. 1992,21 151. 90 R.Aebersold E.1.Bures M.Namchuk M. H. Goghari B. Shushan and T. C. Covey Protein Sci. 1992,1 494. 91 J. E. Matusik M.G. Leadbetter C.J. Barnes and J. A. Sphon J. Agric. Food Chem. 1992 40 439. 92 S.H. Hoke 11 J.M. Wood R.G. Cooks X.H. Li and C.J. Chang Anal. Chern. 1992,64 2313. 93 F.M. Rubino and L. Zecca Biol. Mass Spectrom. 1992 21 109. 30 C. P. Ball and P. J. Derrick selected ion monitoring has been employed to detect cortisol and cortisone in human plasma. C2H2]cortisol and [2H,]cortisone were used as internal standards and the determination was based on the [M-3I] fragment ions of the rnethoxine-trimethyl- silyl derivative^.^^ Macrolide antibiotics have been examined by capillary zone electrophoresis combined with ES. Increasing the ES skimmer voltage gave structurally significant fragment ions.This method gave a better limit of detection than any other currently in use.95 Tandem mass spectrometry has been used to demonstrate that halopridoe@ a neuroleptic drug is metabolized into at least eight different compounds.96 The purification of saxitoxin the parent compound in the family of toxins responsible for paralytic shellfish poisoning (PSP) has been monitored using flowinjection analysis and capillary electrophoresis-mass spectr~rnetry.~ Tandem mass spectrometry was used to obtain structural information. Quilliarn ef aLg8have analysed okadaic acid and dinophysistoxin-1 ,the principle toxins implicated in cases of diarrhetic shellfish poisoning by a liquid chromatography/mass spectrometric method which provided a mass detection limit of 0.4 ng for each toxin.The trace level analysisg9 of sulfonylurea herbicides has been reported using thermospray. Enan- tiomers of chiral octachloranes in tissue samples from aquatic vertebrates in Antarctica"* were separated using chiral high resolution GC and detected by electron capture negative ionization mass spectrometry. TaxoP and related diterpenoids have been analysed by microbore BPLC coupled with electr~spray.'~~ 100 pg of all taxanes were readily detected using secondary ion monitoring. Vitamin D metabolites have been characterized by cycloaddition with 4-phenyLl,2,4-triazoline-3,5-dione, followed by continuous-flow FAB-MS.'02 The spectra are dominated by peaks corresponding to a protonated molecule and by side-chain fragments.The siderophores of the fire blight pathogen Erwinia arnylouoria a group of proferrioxamines have been detected and characterized by LC-ES. In addition six hydroxamate compounds were characterized and another five detec- ted.'03 Tomatine a glycoalkaloid has been identified at the femtomole level by four-sector tandem mass spectrometry and scanning-array detection. 'O4 CapilIary eIectrophoresis combined with electrospray was used to make the intriguing discovery that the venom of the black mamba contains at least 70peptides and has a molecular mass range of 5OOO-9000 Da.'" Peptides and Proteins-Mass spectrometryis now fairly well established as a refiable 94 H. Shibasaki I. Arai T. Furuta and Y. Kasuya J. Chromotogr.I992,576,47. 9s C.E.Parker J. R. Perkins K. B. Tomer Y. Shida K.O'Hara and M. Kono,J. Am. SOC. Mass Spectrom. 1992 3 263. 96 J. Fang J. W. Gorrod M. Kajbaf 3. H. Lamb and S. Naylor,J. Mass Spectrorn.Ion Processes 1992,122 121. 97 S.Pieasance S. W. Ayer M. V. Laycock and P. Thibault Rapid Commun. Mass Spectrom. 1992,5 14. 98 M.A.Quilliarn S. Pleasance and J.C. Marr Rapid Commun. Mass Spectrom. 1992 6 121. 99 M.L. Shalaby F. Q. Bramble Jr. and P. W. Lee,J. Agric. Food Chem. 1992,40 513. 100 H.R,Buser M.D. Mueller and C. Rappe Enuiron. Sci. TechnoL 1992,26 1533. 101 F. Bitsch W. Ma F. Macdonald M. Nieder and C. H. L. Shackteton J. Chromntogr. Biomedical Appl. 1993,615 273. 102 B. Yeung P. Vouros,and G. Satanarayana Reddy J. Chromatogr. 1993,645,115.103 G.J. Feistner D.C. Stahl and A. H. Gabrik Org. Mass. Spectrom. €993,28 163. f 04 S. Evans R. Buchanan A. Hoffman F. A. Mellon K.R. Price S. Hall F. C. WaIls A. L. Burlingame S. Chen and P.J. Derrick,Org. Mass. Spectrom. 1993 28 289. 105 J. R. Perkins C. E. Parker and K.B. Torner Electrophoresis (Weinheim) 1993,14. Physical Methods and Techniques -Part (ii) Mass Spectrometry and sensitive method of sequencing peptides. The rapid deveIopment of ES and MALDI of proteins and advances in techniques for interfacing mass spectrometers with separation methods such as capillary zone electrophoresis(CZE)has led to more and more mass spectrometry being undertaken in the protein field. Antigens recognized by T-cells are expressed as peptides bound to major histocom- patibility complex (MHC) molecuIes.Microcapillary HPLC-ES tandem mass spec- trometry has been used to sequence subpicomolar amounts of peptides isolated from the MHC molecule HLA-A2.1.'06 Of 200 species quantitated eight were sequenced and four found in cellular proteins. All were nine residues long and shared a distinct structural motif. The enzyme 6-pyruvoyl tetrahydropterh synthase which occurs at very low levels in the metabolic disorder atypical phenylketonuria was purified and characterized from salmon liver digested and sequenced by tandem mass spec- trometry.'*' Biemann and coworkers'a8 showed from the m/z ratio of ions of the tryptic peptide of myoglobin encompassing the disputed amino acid 122 (previously commonly held to be asparagine) derived from horse heart and horse skeletal rnyoglobins the apomyogIobin of the latter and the tryptic and chymotryptic peptide of sperm whale myoglobin that amino acid 122of the myoglobin tryptic peptide is aspartic acid rather than asparagine.This finding was confirmed by the collision-induced dissociation spectra of the EM + HI+ ions of the tryptic peptides. Thus the correct relative molecular mass of horse myoglobin is 16 951.49 (not 16950.5 as previously reported) and that of the sperm whale protein is 17 199.91 (not 17 199 as previously reported). Since myoglobin is used as a common mass calibrant this finding is of importance. Destruxins (cyclodepsipeptides) were sequenced using FAB by Lange st a1.,'*' with deuteriation used to overcome problems caused by isobaric fragment ions.Lumb et a[.' * have studied D52S hen lysozome oligosaccharide complexes by ES. They found that in the spectrum of a mutant form with a catalytically important residue Asp-52 replaced by serine the most intense peaks arise from uncomplexed protein indicating that dissociation takes place in the mass spectrometer. Peaks from minor species corresponding to complexes between the protein and oligosaccharide were also observed.The leucine zipper found in several DNA-binding proteins has been shown by HPLC-ES and tandem mass spectrometry to dimerize both in solution arid in the gas phase. These dimers are stable in the gas phase for minutes."' The infectious scrapie prion PrP'" has been sequenced from endoprotease digests by mass spectrometry and Edman degradation data.I Species-selective effects have been observed in the production of peptide ions by ES. For Arg-Arg-Arg and Lys-Lys in methanol-water (80:20 by volume) the relative intensities of (Ch,OH,)+ ions were found to decrease faster than those of other ions with distance from the capillary tip to Io6 D. F. Hunt R.A. Henderson J. Shabanowitz K. Sakaguchi H. Michel N.Sevilir A. L. Cox E. Appella and V. H. Engelhard Science (Washington D.C.) 1992 255 1261. lo' C. R. Hauer W. Leirnbacher P.Hunziker F. Neukeiser N. Blau and C. W. Heimann Biuchem. Biophys. Res. Cammun. 1992 182 953. lo' J. Zaia R.S. Annan and K. Biemann Rapid Commun. Mass Spectrom. 1992,5 32. Io9 C. Lange C. Mulheim A. Vey and M. Pais Biol.Mass Spectrom. 1992 21 33. 'lo K.J. Lumb R.T. Aplin S.E. Radford D. B. Archer D. J. Jeenes N. Lambert D.A. MacKenzie C.M. Dobson,and G. Lowe FEBS Lerters 1992,2% 153. I' I G.S. Gorman and J.I. Amster Org.Mass. Spectrom. 1993 28 437. N. Stahl M.A. Baldwin D.B. Teplow L.Hood B. W. Gibson A. L. Burlingame and S. B. Prusiner Biochemistry 1993 32 1991. 32 C. P. Ball and P.J. Derrick interface plate. These ions are believed to have maximum intensities in the central region of the spray cone whilst ammonium and singly charged oligopeptide ions are found in the peripheral region. The results are interpreted in terms of the volatility of ions in the charged liquid A detailed study of the field desorption of valinomycin found that the ratio of the molecular ion to the protonated molecule was independent of the emitter heating current and the nature of particular additives to the solution.In contrast the presence of the [M + Na] + ions was very strongly dependant on the heater current. There was also found to be no relationship between the abundance of cationized species and the selectivity of valinomycin for monovalent species in solution.' l4 Tandem mass spectrometry of valinornycin has been studied with a number of ionization methods; these show a marked difference between [M + Na]' spectra following different methods of ionization."' SmalI peptides react with alkaline earth metals under FAB conditions to form metal-bis(peptide) complexes [2 peptide + metal -3 H]-. The metal ion binds to the deprotonated C-terminal carboxylate group of both peptides and to a deprotonated amide nitrogen of the constituent peptides.This gives rise to fragments containing metal ions tightly bound to the C-terminal end of the peptide with few N-terminal fragment ions.' l6 A similar study has been described for tripeptides. I' Fragmentation mechanisms for the formation of several commonly occurring product ions in high-energy collision-induced decomposition spectra of [M + Ca-H]+ ions have been evaluated by using deuterium-labelled peptides.' I8 The [M -171peak observed in the muitiphoton ionization mass spectra of dipeptides has been explained as the elimination of ammonia from the molecular ion. The [M-181 peak is generated from the ionization of the thermally decomposed dipeptide.' l9 Tripeptide stereoisomers have been distinguished successfully by tandem mass spectrometry on a hybrid instrument by using CAD.The tripeptides were of the form X-L-Pro-L-Phe where X is L-AIa D-AI~ L-As~ or asp. The differences in fragmentation were correlated with force-field calculations on hydrogen-bonded tautomers."* Abundant ions due to the cleavage of Asp-Pro and Asp-Xxx ions following MALDI have been observed by TOF. Using four-sector tandem mass spectrometry abundant metastable decomposition of Asp-Pro bonds takes place in larger peptides and proteins. The implication is that the Asp-Pro bond is especially The gas-phase basicities of 22 peptides have been estimated by using MALDI to generate prutonated peptides which were then reacted with reference compounds to bracket the gas-phase basicity.Neutral peptides were desorbed using substra-te-assisted laser desorption and reacted with protonated references to confirm proton affinity values. The results are consistent with an intramoIecuIar hydrogen bond between the N-terminus nitrogen and the arnide carbonyl oxygen of a dipeptide which 'I3 K. Hiraoka K. Murata and I. Kudaka Rapid Commun. Muss Spectrom. 1993,7 363. li4 M.M. Sheil and P.J.Derrick Org. Mass. Spectrom. 1992 27 1OOO. 'I5 M. M. Sheil G.W. Kilby J. M. Curtis C. D. Bradley and P.J. Derrick,Org. Mass. Spectrom. 1993,28 574. 'I6 P. Hu and M.L. Gross,J. Am. Chem. SOC. 1992,114,9161. 'I7 P. Hu and M.L. Gross J. Am. Chem. SOC. 1992,114 9153. 'I6 H. Zhoa and J. Adams Int.J. Mass Spectrom. Ion Processes 1992 125 195. 'I9 D. S. Nagra J. Y. Zhang A. P. L. Wang and L. Li Int. J. Mass Spectrom. ion Processes 1992,116 127. 12' B. L. Schwartz R. D. McQain B. W. Erickson and M. M. Bursey Rapid Commun. Mass Spectrom. 1993 7 339. W. Yu 5.E. Vath M. C. Huberty and S.A. Martin Anal. Chem. 1993 65 3015. Physical Methods and Techniques -Part (ii) Mass Spectrometry 33 increases in strength with the strength of the basicity of the C-terminal amino acid.lZ2 Bean and Carr used tandem mass spectrometry and high-energy CAD to sequence through the cystine bridge of intermolecularly disulfide-bonded peptides. 23 Using this method they found that a characteristically-defined triplet of intense fragment ions is observed. FAB tandem mass spectrometry of protonated and metal-cationized peptides was foundlZ4to give evidence of intramolecular rearrangements in the gas phase."0 was used to label the C-terminal carboxyl group and suggested a mechanism where the C-terminal amino acid group is lost with retention of the original carboxyl residue. Using two steps of tandem mass spectrometry (MS/MS/MS) analysis the intermediate formed in the process was found to be the same for both the ["O,] and the [180]-labelIed rearrangement products. The probable intermediate was concfuded to be almost certainly cyclic. The fragmentation of the peptide luteinizing of hormone releasing-hormone measured in plasma desorption mass spectrometry (PDMS) and keV-atom bombardment has been compared with the field desorption (FD) mass Kenny has proposed a mechanism for the formation of y ions in the collision-induced dissociation spectra of protonated peptides produced by FAB,l z6 in which a hydrogen atom attached to nitrogen migrates during the amide bond cleavage.Evidence was obtained by Ackermann et a/. 27 for a lysine-specific fragmentation in FAB of peptides. Fragment ions from peptides containing lysine (or other amino acids with a free amino group on a side chain) were found 16Da below the b ions normally resulting from C-terminal fragmentation. Using liquid secondary ion mass spec- trometry (LSIMS) the peptide somatostatin-14 (SS-14) was found to undergo unsymmetrical disulfide bridge cleavage. The mechanism for c" ions from protonated peptides produced during fast atom bombardment and collisonal activation has been eiucidated.Neither the carboxylic proton nor a hydrogen atom from a nitrogen is involved in the process of hydrogen migration that gives rise to the c" ion. The most feasible position from which the hydrogen originates is that at the first C-atom in the adjacent amino acid side chain.'. 28 FAB-MS/MS of a disulfide-containing enkephalin [Pen]-enkephalin gives a large number of fragment ions in contrast to other disulfide peptides. Most of the fragments are due to backbone cleavages with unsymrnetric cleavage of the disulfide bond giving charge retention at the N-terminus; the fragment ions rarely include a sulfur atom. The N-terminal ethyltriphenylphosphonium derivative however shows very little frag- mentation due to its suggested charge localization at one end of the peptide.1.29 The disulfide bridges in recombinant human macrophage-stimulating factor a 49 kDa homodimeric protein have been assigned through FAB after cleavage using BrCN.Papayannopoulos and Biemann have suggested a reason for the non-detection of 122 G.S. Gorman and J.I. Amster J. Am. Chem. Suc. 1993 115 5729. M.F. Bean and S.A. Carr Anal. Biochem. 1992 201 216. K. D. Ballard and S.J. Gaskell J. Am. Chem. Soc. 1992 114 64. IZ5 A. G. Grey H. Bennich and P. J. Derrick,Ausr. J. Chem. 1992,45,403. P.T.M. Kenny Rapid Commun. Mass Spectrom. 1992,6,95. B. L. Ackermann R. J. Barbuch J. E. Coutant J. L. Krstenansky and T. J. Owen Rapid Commun. Muss Spectrom.1992,6 257. W.D. Van Dongen C.G. De Koster W. Heerma and J. Haverkamp Rapid Commun. Mass Spectrom. 1993,7,241. '29 Y. S. Chang D. A. Gage and J.T. Watson Biol. Mass Spectrom. 1993 22 176. 130 M.O. Giocker B. Arbogast J. Schreurs and M. L. Deinzer Biochemistry 1993 32,482. 34 C.P. Ball and P. J. Derrick components in peptide mixtures in FAB-MS. This phenomenon has always been attributed to the suppression of ionization of some of the mixture components by other components; a change in the sample probe temperature has been suggested as a method of overcoming this effect. I Derivation has been used to increase negative ion sensitivity and positive ion sequence information for LSIMS of peptides. The analyte is acylated at unprotected N-termini tyrosine and lysine by application of pentaf- luorobenzoyl The obervation that certain preparations for FAB yield an intense puIse of peptide ions at the start of ionization hasprompted the development of a source incorporating a probe that permits mechanical movement of the sample stage and mimics a pulsed atom-beam.Following bombardment initiation sample ions are preferentially desorbed with respect to matrix ions. Using an array detector the system allows significantly enhanced sensitivity up to an improvement in the detection limit of three to four orders of magnitude.133 A computer program has been developed specificaIly for interpretation of four-sector tandem mass spectra of peptides.'34 The sequencing algorithm uses a pattern based on the polymeric nature of peptides to classify spectra1 peaks.An algorithm has been described which uses both Edman and mass spectrometric data for the simultaneous detection of the amino acid sequences of several peptides in a mixture. The algorithm utilizes Edman data to detect all hypothetical sequences with a catculated mass equal to the observed mass of one of the peptides present in the mixture. These sequences are then assigned figures of merit according to how well each of them accounts for the fragment ions in the tandem mass spectrum of the pe~tide.'~~ Carbohydrates.-The analysis of carbohydrates by mass spectrometry is receiving considerable attention partly because of the introduction of the ES and MALDI techniques. Harvey has reviewed the roIe of MS in glycobiology,136 with particular emphasis on oligosacc harides and glycoconj ugates.Chai er c-11.'~' identified22 neutral 0-linked oligosaccharides in bovine submaxilli- ary gland mucin glycoprotein using LSIMS. The sequences and linkages of sub-nanomolar amounts of thyroid gland oligosaccharides have been confirmed using FA3 and MS/MS. The [M + HI+ and [M + Na]' ions were compared revealing several ions in the [M + NaJ+ spectra not present in the appropriate protonated form in the EM + HI+ spectra. The utility of metal attachment for MS/MS analysis of oligosac- charides has been demonstrated by Leary and coworkers who used dilithiated disaccharides labelled with l80and 'H to determine the Iinkage positions of three isomeric disaccharides.' 38 Centrifugal size-exclusion chromatography and membrane filtration have been used to remove saIts from carbohydrates prior to analysis resulting in an increase in the sensitivity and in the number of structurally significant peaks.139 Ammonia desorption chemical ionization MS of peracylated gentiobiose and 13' I.fapayannopoulos and K. Biemann int. J. Mass Spectrorn. Ion Processes 1992,122,43. 13' J. P. Kiplinger L. Contillo,W. L. Hendrick,and A. Grodski Rapid Commun. Mass Spectrom. 1992,6,747. 133 A. N. Tyler L.K. Romo M. H. Frey B. D. Musselman J. Tamura and R.B. Cody J. Am. SOC.Muss Spectrom. 1992 3 637. 134 W. M.Hines A. M. Falick A. L. Burlingame and B. W. Gibson J. Am. SOC.Mass Specfrorn. 1992,3,324. 135 R.S.Johnson and K. A. Walsh Protein Sci. 1992 1 1083.D. J. Harvey Glycoconjugate J. 1992 9 1. 13' W.Chai E. F. HounselI G.C. Cashmoqe J. R.Rosankiewicz,C.J. Bauer J. Feeney T. Feizi and A. M. Lawson Eur. 1.Biochem. 199? 203 257. A. Staempfli 2.Zhou,and J. A. Leary J. Org. Chern. 1992 57 3590. 139 T. F. Chen H. Yu,and D. F. Barofsky Anal. Chem. 1992,64 2014. Physical Methods and Techniques-Part (ii) Mass Spectrometry isotopically labelled forms showed that the (M + NH -42f+ ion is not formed directly from [M + NH,J* by loss of ketene but by way of a nucleophilic acyl substit~tion.'~~ FT-ICR has been used to examine the origin of fragment ions created during desorption-ionization of disaccharides avoiding the interference of matrix Three major product ions were observed corresponding to loss of water loss of monosaccharide and a combination of both.Mass spectrometry of high-rnannose oligosaccharides after trifluoroacetolysis and periodate oxidation was examined by FAB and electron irnpact.l4* The conditions used were designed to degrade terminal N-acetylglucosarnine residues and binding positions between monosaccharide resi- dues were deduced. GC-MS has been used to study the carboxymethyl groups in 0-(carboxymethy1)ated(1 -,3)-a-~-glucans and (1 43)-a-~-glucans. 143 The results showed a distribution characteristic of the glucatn type especially at position 2 on the D-glucosyl residues. Three thyroid gland oligosaccharides have been characterized by FAB-MS/MS. The saccharides were derivatized with p-aminobenzoic acid ethyl ester and detected in subnanomolar quantities.The [M + Na] + ions in some cases allowed assignments of the linkage positions between the sugar residues.'44 MS/MS has been used to analyse the B -+ C linkage position in neutral permethylated trisaccharides of the formulae galactose(B-1-+ 4)glucose(/3-1+ X)glucose where X = 3 4 and 6. The relation of daughter ion to parent ratios was used to predict the linkage position in glu- cose@-1-+ X)gl~cose.'~~ This method has been used for the [M + Na]' ions of permethylated oligosaccharides. The linkage positions in one compound may be detected by the presence or absence in a single spectrum of specific fragment ions arising from the cIeavage of two ring bonds. The behaviour of the [M + Na] +-ions of permethylated oligosaccharides at low energy leads to preferential cleavage of the glycosidic linkages which become more efficient if argon replaces helium as the collision gas.'46 Distinctions between the linkage types 1 -2 1 + 3 and 1 + 4 of xylobioses can be achieved on the basis of the unimolecular decomposition spectra of the oxonium ions of the per-0-acylated methyl glycosides.This allows the detection of linkages between xylose residues. 14' Ohgosaccharides have been analysed using on-line liquid chromatography/ther- mospray mass ~pectrometry.'~~ Molecular mass information on oligomers of up to a degreeof polymerization of 10was obtained using a mobile phase containing 0.1 mmol sodium acetate which was compatible with thermospray ionization and gave sodiated and disodiated ions without fragmentation.Van der Greef and coworkers'49 have shown how thermospray and ES are useful for the detection of intact oligosaccharides using selected ion monitoring. The on-line coupling of high-performance anion- ''' J. M. Peltier R. W. Smith D. B. McLean and W. A. Szarek Org. Mass. Spectrorn. 1992 27 31. 14* J. A. CarroIl and C.B. Lebrilla Org. Mass. Spectrom. 1992 27 639. '02 P. Lipniunas A. S. Angel K. Erlansson F. Lindh and B. Nilsson Anal. Biochem. 1992 ZOO 58. S. Ukai I. Yoshida A. Honda K. Nagai and T. Kiho Carbohydr. Res. 1992 224,201. D.A. Gage E. Rathke C. E. Costello and M. Z. Jones Glycoconjugate J. 1992,9 126. E. Yoon and R. A. Laine Biol. Mass Spectrom. 1992,21,479. J. Lemoine B.Fournet D. Despeyroux K.R. Jennings R. Rosenberg and E. de Hoffrnann J. Am. SOC. Mass Spectrom. 1993 4 197. L. Blok-Tip A. van der Kerk-van Hoof' W. Heerma,J. Haverkamp V. Kovacik and J. Hirsch Biol. Muss Spectrom. 1993,22 474. W. M. A. Niessen R. A. M. Van der Boeven J. Van der Greef H. A. Schols and A. G. J. Voragen Rapid Commun. Mass Spectrom. 1992 6 197. W. M. Niessen R. A.M. Van der Hoeven and J. Van der Greef' Org. Mass. Spectrom. 1992,27 341. 14' 36 C.P.Ball and P. J. Derrick exchange chromatography and thermospray MS has been described for the analysis of neutral and acidic oligosaccharides obtained as degradation products of cell wail dige~tion.''~ Lipids and Steroids.-Negative-ion mode FAB/MS/MS has been applied to 24 naturally occurring and synthetic diacylglycerylphosphocholines.'51 The method of selecting EM -151-as the parent ion and using the relative abundances of the carboxylate daughter ions to distinguish the esterification positions was found to be unreliable in the cases where the fatty acid group at S,1 was much larger than that at 5,2.By use of the [M -861-ion as the parent the relative intensities of the detected fragments resulting from the Ioss of the free fatty acids at SNland S,2 were found not to depend on the nature of the fatty acid groups present. Van Dorsselaer and coworkers have used negative FA3 on phosphodiesters linked to oxysterols and nucleosides.' 52 The effect of structure on the electron-capture mass spectrometric response of steroids has been in~estigated.'~~ Combinations of double bonds carbonyl groups epoxides and halogens with a steroid nucleus were correlated with their elec- tron-capture negative ionization responses.An epoxy keto steroid has a relative response 40 times greater than the corresponding enone. A method to reduce degradative losses of steryl fatty acyl esters in high-temperature GC-MS employs selective deuteriation of the double bonds in the fatty acid moiety using a homogeneous catalyst.ls4 GC behaviour is improved and structural inforrna- tion is preserved by labelling each doubIe bond present in the original moiety. 16-Androsterones and their isomeric saturated analogues have been analysed by GC-MS using selected ion monitoring.' 55 Desorption chemical ionization triple quadrupole mass spectrometry has been used to study the coliision-induced dissociation of permethylated glycosphingolipids.The dissociation of positive ions produced mainIy sugar sequence ions. A rearrangement reaction was suspected €or unsaturated ceramides as no fatty acid daughter ions were seen for compounds with unsaturated bonds at the C-4-C-5 position.' 56 Lipids from Entobacter agglornerans a Gram-negative bacterium found in cotton have been identified using plasma desorption (PI))-MS. 57 FAB-MS/MS has been established as a useful technique for the identification of intact glycexophosphatidylethanolamine phospholipids giving information about the polar head group and about fatty acid constituents. Scanning fur a loss of 141mass units was the strategy used to confirm the presence of a phosphoethanolarnine polar head group but this scan has now been found to discriminate against the common subgroup of phopholipids with a 1-0-alkyl-1'-enyl linkage (the plasmalogens) and against a 1-0-alkyl ether specie^."^ Is* W.M. A. Niessen R. A. M. Van det Hoeven J. Van der Greef H. A. Schois,G. Lucas-Lokhorst A+G.J. Voragen and C. Bruggink Rapid Commun.Mass Spectrom. 1992,6,474. Is* Z. H. Huang D. A. Gage and C.C. Sweeley J. Am. SOC. Mass Spectrom. 1992,3 71. X. Pannecouke A. Van Dorsselaet and B. Luu Org. Muss.Spectrom. 1992,27 140. 153 H.K. Mayer W. Reusch and J. T. Watson Org. Mass. Spectrom. 1992 27 560. Is' R.P. Evershed M. C.Prescott and J. L. Goad .I.Chromatogr. 1992 590 305. T.K. Kwan D. B. Gower D. J.H.Trafford and H. L. J. Makin Bid. Mass Spectrom. 1992 21 160. J. S. Duh and G.R. Her Bid. Mass Spectrom. 1992 21 391. 15' R. B. Cole L.N. Domeksmith C. M. David R. A. Laine and A. J. DeLucca Rapid Commun. Mass Spectrom. 1992 6 616. 15' K.A. Kayganich and R. C. Murphy Anal. Chem. 1992,64 2965. Physical Methods and Techniques -Part (ii) Mass Spectrometry 37 DNA and Nucleotida-McLuckey et a).' 59 have examined multiply charged ions derived from ES ionization of the sodium salts ofsmall oligonucleotides (n = 4 to 8) by MS/MS in a quadrupole ion trap. The ions were observed to dissociate with high efficiency. In every case the most facile reaction was the loss of the adenine anion followed by the cleavage of the C-3-0 bond of the phosphodiester linkage of the sugar from which the adenine had been lost.The collision-induced dissociation of protonated adenine and of rnonomethylated adenines has been studied by MS/MS spectrometry and isotopic labelling.' 6o A DNA quadruplex has been detected by negative-ion ES at a low nozzle-skimmer bias (-150V) but at higher bias values it is not seen.The complex is only seen in lOmM sodium phosphate (pH 7.5) with 0.1 mM EDTA. Without the metal only single-stranded DNA is seemi6' MALDI ofoligodeoxythyrnidylic acids has been investigated by Huth-Fehreet a].;16* using ferulic acid sinapinic acid or 2,5-dihydroxybenzoic acid as matrices for pure oIigonucleotide P~(T),~ and a mixture of pd(T), through pd(T)18. 2,5-dihydroxyben- zoic acid gave the least fragmentation and adduct formation and highest mass resolution.3-hydroxypicohic acid has been evaluated as a matrix far MALDI of oligonucleotides and found to show good characteristics with regard to signal-to-noise ratio mass range available and ability to handle mixed-range oligomers. Spectra taken at 266 nm were found to give the best results in negative-ion mode.163 RNA oligomers and transcripts up to 104nucleotides iong have been analysed successfuIly by MALDI. RNA is found to be more stable to MALDJ than oligothymidyIic acids as the N-glycosidic bond seems to be broken during the desorption and bases are MALDI has been used to determine the molecular masses ofsynthetic methylphosphon- ateoligodeoxyribonucleotidesofup to 18 nucleotidesin length.16' TOFmass spectra of DNA fragments as massive as 18 OOO Da have been produced using laser ablation.'66 Low picomole levels of nucleoside-arcinogen adducts were detected using FA3 and MS/MS.167Chemical derivatization by trimethylsilyl neutral Ioss scans and daughter ion scans were all used to probe the structural specificity of the adducts.FAB and MS/MS have been used to examine the interactions between the anticancer drug cisplatin and DNA.168FAB gives useful structural information and high energy collisianal-induced dissociation shows the location of the platinum binding sites. For aglycon-halogenated nucleosides an inverse linear reIationship exists between the extent of dehalogenation during FAB and the electron affinity of a given nucleoside. 69 159 S.A.McLuckey G.J. Van Berkel and G.L. Glish J. Am. SOC. Mass Spectrom. 1992 3 60. 160 C.C. Nelson and J.A. McCloskey J. Am. Chem. Soc. 1992,114,3661. 161 D. R. Goodlett D. G. Camp IT C.C.Hardin M.Corregan and R. D. Smith Biol. Mass Spectrom. 1993 22 181. 16' T. Huth-Fehre J.N. Gosine K. J. Wu and C.H. Becker Rapid Commun. Mass Spectrom. 1992,5,209. 163 K. J. Wu A. Steding and C. H. Becker Rapid Commun. Mass Spectrom. 1993,7,142. E.Nordhoff R. Cramer M. Karas F. Hillenkamp F. Kirpekar K. Kristainsen and R. RoerpstorfF Nucleic Acids Res. 1993,21 3347. 16' T.Ke0ugh.T. R. Baker R. L. M. Dobson,M.P. Lacey T. A. Riley J. A. Hasselfield and E. P. Hesselberth Rapid Commun. Mass Spectrorn. 1993,7 195. *" P. Williams D. Schieltz R. W. Nelson C.W+ Chou C.W. Luo and R.Thomas in 'Proceedings of Advances in DNA Sequencing Technology' 1993 p. 86. 167 M. S. Bryant J.O. Lay Jr. and M. P. Chiarelli J. Am. SOC. Mass Spectrom. 1992,3 360. C,E. Costello K. M.Comess A. S. Plaziak D. P. Bancroft and S.J. Lippard int. J. Mass Spectrorn. Ion Processes 1992,122,255. S. M. Musser and J. A. Kelley Org. Mass. Spectrorn. 1993,28,672. 38 C. P. Ball and P. J. Derrick Narcotics and Drugsof Abuse.-Mass spectrometry is recognized as being a formidable tool for the analysis of controlled substances particularly in conjunction with GC and a wealth of information on techniques for the analysis of narcotic compounds in particular has been published. A review of opiate MS has been given by Cone and Darwin.I 70 Using GC-MS in electron impact (EI)mode the metabolites of danazoI an anabolic steroid banned by the International Olympic Committee were detected in a urine sample.Ethisterone was identified as a nonconjugated metabolite and the two stereoisomersof 2-hydroxymethylethisteronewere observed one in a conjugated form and the other primarily unconjugated.’ 71 Derivatives of seven commonly used sympathomimetic amines and two designer amines were isolated from urine separated from amphetamine and methamphetamine by GC and detected by MS using seIected ion monitoring. False positive were only seen for methamphetamine and only when >5 pg of ephedrine was present in the ~arnples.”~ Several methods for introduction derivitization and ionization of lysergic acid diethylamide (LSD) iso-LSD and N-dimethyl-LSD in body fluids have also been evaluated for MS/MS.Fragmentation pathways derived from low-energy collision-induced dissociation of LSD and derivatives have been proposed. Positive ion chemical ionization of these compounds provide a high degree of specificity for their identification in blood and urine at low pgml-levels whilst negative ion chemical ionization and GC-MS/MS has been found to be of use in determining rnetab01ites.l~~ 7 Electrospray Electrospray atmospheric pressure ionization and ion-spray are all variations on a common theme. Comparison between ES and MALDI is inevitable but not straightforward. Green’74 has criticized a paper by Allen et al. that sought to compare ES and MALDI for analysis of protein mixtures.In Green’s opinion the paper did not compare the techniques impartially but detracted from the utility of the ES technique. ES was used to show the difference in the conformational states of a zinc-finger DNA-binding protein domain. Evidence for the induction and stabilization of a different conformational state with bound copper as opposed to zinc was revealed by a characteristic shift in the electrospray charge envelope.’ 75 A similar zinc-finger protein that binds to oestrogen was demonstrated to have a high affinity for copper which inhibits its function by the use of E5.l7‘ It was also found that non-covalentIy bound polypeptide and protein dimer ions are relatively common as low level contributions to ES mass spectra. The detection of these compounds requires gentle electrospray conditions yielding low levels of internal excitation but these conditions can lead to artifacts in MS/MS due to incomplete solvation of ions.’77 The haem-apomyoglobin complex which is non-covalently bound and has a mass of 17568Da has been detected by ES at femtomolar quantities.The complex does not fragment under 170 E.J. Cone and W.D. Darwin J. Chromutogr. I992,=,43. D. De Boer E.G. Jing and R.A.A. Maes J. Anat. Toxicol. 1992,16,14. ”* E. M. Thuman M.J. Pedersen R.L. Stout and T. Martin J. Anal. Toxicol. 1992,16,19. 173 CC. Nelson and R.L. Fottz Anal. Chem. 1992,64 1578. 17’ 3.N. Green Biochem. J. i992 284 603. If’ W. T. Hutchens and M. H. Alien Rapid Commun. Mass Spectrom. 1992,6 496. lf6 W.T.Hutchens M.H. Allen C. M. Li and T.T. Yip FEBS Lett. 1992,309,170. 177 R.D. Smith K.J. Light-Wahl B. E. Winger and J.A. Loo Org. Mass. Spectrom. 1992,27,811. Physical Methods and Techniques -Part (ii) Mass Spectrometry 39 kilovolt energy conditions.' 78 Allen and Vestal developed an ES system using heat as a means of desohation and no counterflow of heated gas."' The ability to obtain fragmentation data by collisional-induced dissociation was demonstrated clearly. ES mass spectra of human haemoglobin chains and transferin were acquired on a magnetic sector mass spectrometer.''' The observed isotopic distributions for the haemoglobin ion were in good agreement with the theoretical distribution within a resohtion of 2000. Accurate mass measurements have been obtained for masses in the 500-16000 range using a double-focusing magnetic-sector instrument and ES ionization.Magnetic-field scans and accelerating-potential scans were used and gave mass accuracies in the low ppm range in both positive and negative-ion modes. ES ionization has been used in a study of the reactions of multiply protonated melittin molecule ions. Flowing the ions entrained in gas through a heated metal capillary inlet served as a reaction vessel for measurements of ion reaction rates.IB2 Differences in activation energies found for different charge states were attributed to Coulombic repulsion effects. ES has been used to detect a ternary complex between the dimeric enzyme HIV-1 protease and a substrate-based inhibitor.183 Under denaturing conditions only the monomeric HIV-1 protease could be observed by mass spectrometry (see aIso ref.€84). Using the tightly binding competitive inhibitor JG365 the ternary complex was detected and this was dissociated by raising the declustering potential at the ion sampling orifice. Electrospray has been used to detect and differentiate betweenthe free human H-ras protein and its non-covalently bound GDP complexform. 85 Analysis of recombinant proteins has been performed using high-performance capillary elec- trophoresis interfaced with an electrospray ionization mass spectrometer.186 The detection Iimit was 100 fmol the standard deviation of peak migration times was less than 1YO,and mass assignment was within 1 unit in 22 0o0. The results showed that individually neither CZE nor ES ionization could detect all impurities but coupling enhanced the abilities of both.Oligosaccharides digested from asparagine side chains of glycoproteins have been analysed by ES and MS/MS. a Oligosaccharides containing sialic acids were detected best by negative-ion mode whilst others were best in the positive-ion mode. In positive-ion mode the addition of sodium or ammonium acetate greatly enhanced the ion abundances. MS/MS was used to detect primary structural features of the oligosaccharides. Boyle and Whitehouse coupled an ES source to a reflectron time-of-flight mass spectrometer achieving a resolving power of over loo0 by orientation of the ion source 178 J.A. Loo,A. B. Giordani and H. Muenster Rapid Commun.Mass Spectrom. 1992 7 186. 179 M. H. Allen and M. L. Vestal J. Am Soc. Mass Spectrom. 1992,3 18. Y.Wada J. Tarnura B+D.Musselman D. 8. Kassel. T. Sakurai and T. Matsuo Rapid Commun. Mass Spectrom. 1992,6 9. "' R.B. Cody J. Tamura and B,D. Musselman And. Chem. 1992,64 1561. lS2 M.Busman A. L. Rockwood,and R. D. Smith J. Phys. Chem. 1992,% 2397. lS3 M. Baca and S,B. H. Kent J. Am. Chem. Soc. 1992 114 3992 lS4 U.A. Mirza S. L.Cohen and B.T. Chait Anal. Chem. 1993 65 1. la' A. K. Ganguly B.N.Pramanik A. Tsarbopoulos T. R. Covey E. Huang and S.A. Fuhrman J. Am. Chem. Soc. 1992 114,6559. la6 K. Tsuji L Baczynskj and G.E. Bronson Anal. Chem. 1992,64 1864. Is' K.L. Duffin J.K. Welpy E. Huang and 3.D. Henion Anal. Chem. 1992,64 1440. 40 C.P.Ball and P. J. Derrick perpendicular to the field-free drift region.'*' The instrument was also sufficiently sensitive to allow the routine detection of low picomole quantities of multiply chafged cy tochrornes. 8 Matrix-assisted Laser Desorptlonflonization Matrix-assisted laser desorptionjionization (MALDI) remains one of the fastest- moving branches of mass spectrometry. MALDI in combination with time-of-flight (TOF) has been used for an extremely wide variety of applications normally involving high molecular mass compounds but some work involving smaller molecules has also been performed. The coupling of MALDI and FT-ICR has produced remarkable results; using laser fluences close to the MALDI threshold resolutions of 30000 have been presented for bovine insulin rising to 100OOO for lower mass proteins.Detection of a doubly-charged carbonic anhydrase trimer (m= 87OOO) has also been achieved. Optimum deceleration times for a singly-charged MALDI-generated protein ion are a linear function of Jm when a 9.5 V deceleration potential is used.leg Nelson and Hutchens used MALDI-TOF to examine the affinity of a 25-residue synthetic peptide for copper(I1) ions.'g0 The chemistry was performed on the probe tip and results showed the binding of up to one copper ion per histidine residue. MALDI was also used to identify metal-binding proteins in pruteolytic digests.'" His-tidine-rich glycoprotein a plasma and milk metal-transport protein was purified and digested with trypsin; the fragments were analysed by MALDI-TOF.Copper@) ions were added to the digest mixture and at least one metal-binding peptide was seen. This is the first direct observation by MS of differential peptide-metal digests in protein digest maps. A TUF mass spectrometer with an electrostatic mirror has been used to measure the kinetic energy distributions of molecular ions ejected into an externaI field by MALDI. An energy deficit was observed by this experiment (ix.the ions had less kinetic energy than imparted by the field) of around 24 eV in the typical case of insulin. This deficit increases with molecular ion signal intensity and with molecular weight of the protein. It is aIso larger for negative ions than fur positive ions.'92 Pan and Cotter investigated the initial kinetic energy distributions of arginine-vasopressin molecule-ions gener- ated by UV-MALDI.lg3 The measured molecule ion kinetic energy distribution from vasopressin was found to be much broader than that from gramicidin S and was characterized by a high-energy tail possibly resulting from entrainment of analyte ions in the matrix ions as they leave the surface.Ehring Karas and Hillenkamp have studied a large number of small polar organic molecules which have a strong resonant absorption at the laser ~avelength.'~' In most cases radical cations and ion species formed by single and multiple hydrogen cleavages and additions appeared as strong signals. A model was proposed which explains these features as a product of initiaI photoionization. J.G. Boyle and C. M. Whitehouse Anal.Chem. 1992,64 2084. J. A. Castor0 and C.L. Wilkins Anai. Chem. 1993,65,3015. R.W. Nelson and W.T. Hutchens Rapid Cornrnun.,Moss Spectrom. 1992,6,4. 191 R. W. Nelson W.T. Hutchens and T.T. Yip FEBS Lett. 1992,2% 99. 192 J. Zhou W. Ens K.G. Standing and A. Verentchikov Rapid Commun. Mass Spectrom. 1992 6,671. Y. Pan and R. J. Cotter Org. Mass. Spectrom. 1992 27,3. 194 H. Ehring M. Karas and F. Hilienkarnp Urg. Mass. Spectrom. 1992 27 472. Physical Methods and Techniques-Part (ii) Mass Spectrometry 41 Chan er al. demonstrated that cluster ions extending to very high masses (>500000Da) can be formed and detected from proteins using the liquid 3-NBA matrix for UV-MALDI.'95 Excellent shot-to-shot reproducibility was reported for this liquid matrix.An organic dye added to the matrix was found to increase the efficiency of visible laser systems. The addition of Rhodamine 6G to 3-nitrobenzyl alcohoI allowed the production of protein ions of mRup to 250000 using a 532 nm It has been found that the UV (248nm) desorption of neutral peptide moIecules is greatly enhanced by the application of a thin layer of the sample on top of a UV-absorbing organic substrate (sinapinic acid).' Using this technique gramicidin S is desorbed as an intact neutral with approximately 1eV less internal energy than if desorbed from a metal surface. a-Cyano-4-hydroxycinnaminicacid when used as a matrix,'99 has been found to enhance the tendency of proteins to protonate multiply. Ionic and neutral products of matrix-assisted laser desorption have been detected simultaneously in a TOF mass spectrometer the neutrals being photoionized by coherent UV radiation.The ratio of neutra1:ions has been calculated at around 10OOO :1 with desorption irradiances close to the threshold for ion formation. This ratio decreases with increasing irradiance from the laser beam. This dependence is consistent with a colIisiona1 mechanism for analyte-ion formation during the desorption initiated by photoionization. Matrices giving large signal intensities of directty formed analyte ions gave large intensities of neutral ions as Metastable decay of laser-desorbed ions taking place in the first field-free drift region of a reflectron TOF mass spectrometer has been successfully monitored to obtain structural information from the larger jxptides.201 Fragments from such metastable decay are mass analysed by adjusting the potentials of the ion reflectron according to the kinetic energies of the ions.It has been discovered that post-source decay in MALDI is only 10% with nitrogen as the residual gas compared to An excimer-pumped dye Iaser generating ultra-short pulses (560fs full width at half maximum) in the UV (248nm)and visible (496 nrn) has been used to desorb protein ions from different matrices.203 The existence of a threshold energy for the MALDI of insulin ions by the ultra-short pulses was established and found to be similar to that observed at much longer pulse lengths. The amount of laser energy deposited into the sample not the laser power thus appeared to be important in MALDI.ResuIts obtained frum MALDI work involving bovine insulin in 3-nitrobenzyl alcohol or sinapinic acid matrices suggest that the threshold fluences for the formation of positive and negative ions are the same for a given matrix.204 Laser generated plumes such as those observed in MALDI have been imaged by fluorescence measurements giving concentration maps at time-intervals of 100 19' D.T. W. Chan A. W. Colburn. and P. J. Derrick Urg. Moss. Spectrom. 1992,27 53. 196 D.S. Carnett M.A. Duncan and J. I. Amster Org. Mass. Spectrorn. 1992,27 831. 19' D.S. Carnett M. A. Duncan and J.I. Amster Anal. Chem. 1993,65,2508. 198 J.P. Speir and J.I. Amster Anal. Chem. 1992 64 1041. 199 R. C. Beavis T. Chaudhary and B.T.Chait Org. Mass. Spectrorn. 1992,27 156. 2oo C. D. Mowrey and M.V. Johnston Rapid Cummun. Mass Spectrum. 1993,7 569. B. Spengier D. Kirsch R. Kaufmann and E. Jaeger Rapid Commun. Mass Spectrom. 1992,6,105. '02 B. Spengler D. Kirsch and R. Kaufmann. J. Phys. Chem. 1992,% 9678. *03 P. Demirev,A. Westman,C.T. Reirnann P. Hakansson D. Barofsky B. U. R. Sundqvist Y. D. Cheng W. Seibt and K. Siegbahn Rapid Commun. Mass Spectrom. 1992 6 187. '04 P.Y. Yau D.T. W. Chan P.G.Collis A. W. Colburn,and P.J. Derrick Chern. Phys. Lett. 1993,202,93. '05 T. W.Heise and E. S. Yeung Anal. Chem. 1992 64 2175. 42 C. P. Ball and P. J. Derrick Biemann and coworkers have studied MALDI using a double-focusing magnet- ic-sector mass spectrometer. Pulsed ion signals were generated by irradiation of a mixture of sample and matrix (2,5-dihydroxybenzoic acid) with either an XeF laser (353 nm)or a nitrogen laser (337 nm) and were detected by a focal-plane detector.A resolution (full width at half maximum) of 4500 was achieved for substance P (m/z = 1347.7) 2500 fur CsI cluster ions at m/z = 10005.7 and 1250 for the isotope cluster of horse cytochrome c (m/z = 12360); 11fmol of substance P was detected.'06 A simple method for the off-line coupling of CZE and laser desorption has been described with a detection limit of 1OOfmoI for bovine IactaIb~rnin.~~~*~~~ The challenge of interfacing liquid chromatography with MALDI has been exarnined.'O9 Liquid sample has been introduced directly into the ion source of the mass spectrometer through a capillary.210 Evaporative cooling was used to produce ice at the end of the capiflary which could be extruded using resistive heating.Immobiliz- ation procedures were used to improve the MALDI of hydrophobic cytochrome P-450 proteins containing high concentrations of buffer. A mass accuracy of 0.075% was achieved using bovine serum albumen as an internal standard.21 Smalf fragments of DNA up to a 34-mer have been analysed with various Both positive and negative ions were seen with little fragmentation. A similar series of experiments have been performed on oligodeoxyribonucleotides as various matrices were examined for their efficiency in analysis.213 Mixtures of low picomole amounts of oligodeoxyribonucleotideswith sizes from 6 to 30 units have been e~amined.~ I4 Again molecule-ions were observed again with little or no fragmenta- tion.MALDI has been used to analyse crude synthetic pep tide^.^'^ A highly hydrophobic six-helix bundle template-assembled synthetic protein a 1Prner peptide with an amphiphilic a-helix and a 20-mer thrombin inhibitor were all successfully anaIysed. MALDI was used to verify the insertion of glycine into a C-terminal a-helix thus solving a crystallographic problem in the inability to pinpoint the nature or location of an anomaly in a protein sequence.* t6 MALDI was used to identify rapidly sensitively and sequence-specifically phosphopeptides in unfractionated digests of pho~phoproteins.'~ Beavis produced a review of MALDI covering topics such as sample preparation the nature of the spectra nomenclature and matrices.21 9 Fourier-transform Ion Cyclotron Resonance Electrospray has been combined with Fourier-transform ion cyclotron resonance '06 R.S.Annan H.J. Kochhng J.A. HilI and K. Biemann Rapid Commun.Mass Speccrom. 1992,6 298. 207 T. Keough R.Takigiku M.P. Lacey and M. Purdon Anal. Chem. 1992,64 1594. J. A. Castoro R.W. Chiu C. A. Monnig and C. L. Wilkins J. Am. Chem. SOC. 1992 114 7571. '09 L. Li A. P. L. Wang and L.D. Coulson And. Chem. 1993 65 493. 'lo E.R. Wilhams,G. C. Jones L.L. Fang,T. Nagata R.N. Zare Proc. SPIE-lnt. SOC.Opt. Eng. 1992,172. S. Lewis K. K. Korsrneyer and M. A. Correia Rapid Commun. Mass Spectrom. 1992 7 16. 'I2 K. Tang S. L. Allman and C.H. Chen Rapid Commun. Mass Spectrom.1992,6 365. E. Nordhoff A. Ingedoh R. Cramer A. Overberg 8. Stahl M. Karas F. HiIlenkamp and P. F. Crain Rapid Commun. Mass Spectrorn. 1992,5 771. G.R. Parr M. C. Fitzgerald and L. M. Smith Rapid Commun. Mass Spectrorn. 1992 6 369. 215 V. Steiner K.O. Boernsen M. Schaer E. Gassmann S. Hoffstetter-Kuhn H. Rink and M.Mutter Peptide Res. 1992,5 25. 'I6 L. J. Keefe E. E. Lattman C. Wolkow A. Woods M. Chewier and R. J. Cotter J. Appl. Crystallogr. 1992 25 205. 217 T.T. Yip and W.T. Hutchens FEBS Lett. 1992,308 149. 'la R. C Beavis Org. Mass Spectrom. 1992 27 653. PhysicaI Methods and Techniques -Part fii) Mass Spectrometry 43 (FT-ICR) with the ion source positioned in the bore of the superconducting magnet adjacent to the trapped ion 1x11.~’~ An electrospray current of 375 pA could be detected from gramicidin S at the cell which is two orders of magnitude higher than an external ion source.Five stages of differential pumping within a series of concentric tubes of increasing radius were used to reduce pressure to lom7torr in the trapped cell. Wilkins and coworkers explored the utility of ‘screened’ electrostatic ion trapping techniques. The observed rate of change of ion cyclotron resonance (ICR) frequency with trapping potential is independent of mass and charge fin the range of 1185-17 OOO Da) and using a magnetic field of -7 T the electric potential within a screen cubic trap is reduced decreasing frequency shifts as a function of trapping potential by a factor of 25. The average resolution for a bovine insulin spectrum was 10OO0.220 Hofstadler and Laude have interfaced an electrospray ionization system with FT-ICR.In their system the electrospray occurs at atmospheric pressure in a 1.5Tfield and the FT-ICR detection takes place 25cm away at 3.0Tin one or two cells separated by a conductance limit and maintained at a pressure differential of 5 x lo-’ and 2 x torr. The trapped ion cell wits filled up to the ion space charge limit within a few hundred milliseconds. The rate of ion accumulation is independent of background pressure; hence the primary trapping mechanism is not solely colIision dependent.22 Trapped ion cells which substitute open rectangular trapping electrodes for trapping plates perpendicular to the magnetic field have been evaluated.z2z Radical trapping electric fields are somewhat larger in the centre of the open cells but axial excitation fields are a factor of two smaller compared with the closed cell.Axial ejection is significantly reduced in the open celI compared to the closed cell. The question of poor high-mass (high m/z) performance in FT-ICR has been addressed.z23 Theoretical calcuIations and experimental data showed the existence of resonances involving the z-motion and the radid motion of the ion which result in energy transfer between modes expansion of the ion cloud and a signal loss. Polypeptide ions formed by MALDI have been found not to be in thermaI equilibrium with their surroundings but to exhibit a non-BoItzrnann initial ion velocity distribution about a most probable ion velocity which is independent of polypeptide mass.Radical and axial m/z upper limits and optimum trapping potentials were derived and discussed.224 Analytical expressions fur the probability ofradial or axial loss of thermal ions from a hyperbolic ion trap were developed and gave rise to the observation that the probability of radial ion loss increases with m/z ratio and ion thermal energy whilst axial ion loss is inversely proportional to trapping potential and directly proportional to thermal energy. This model is based on the assumptions that non-interacting ions are formed initially along the trap y axis with a Maxwell-Boltzrnann velocity distribution and trapped by a quadrupolar electrostatic potentiaLZz5 The absoiute number of trapped ions that produce a time-domain signal in FT-ICR has been estimated by comparing the experimentally observed signal voltage to that calculated ”’S.A. Hofstadler and D. A. Laude Jr. Anal. Chem. 1992,64 569. ”* J.A. Castoro C.Koster and C. L. Wilkins Anal. Chem. 1993,65 784. ”’ S.A. Hofstadler and D,A. Laude Jr. J. Am. SOC.Mass Spectrom. 1992 3 615. 12’ S.C. Beu and D.A. Laude Jr. int. J. Mass Spectrom. Ion Processes 1992 112 2. 223 C.L. Holliman D. L. Rempel and M. L. Gross J. Am. SOL Mass Spectrom. 1992,3,460. 224 T.D. Wood,L. khweikhard and A.G. Marshall Anal. Chem. 1992,64 1461. 225 M. A. May P. B. Grosshans and A. G. Marshall Int. J. Mass Spectrom. Ion Processes 1992 120 193. 44 C.P. Ball and P. J. Derrick for a single ion orbiting at the ICR orbital radius of the ion packet.This gives an estimate of -177singly charged ions in a cubic trap at 3.0T.226 Detection limits have been reduced by subjecting a single population of multiply charged protein ions formed by ES to multiple FT-ICR without promoting ion loss from the trapped ion cell. This process is non-destructive and allows at least 250 consecutive remeasurements of a single population of protein ions. A 25 :1 signal :noise ratio has been observed for 30fmol of bovine albumin di~ner.~’~ A two-dimensional charged-disk model was used to explain Coulomb-induced frequency shifting in FT-ICR MS.228 The model consists of a uniformly charged disk whose excited cyclotron motion is perturbed by another uniformly charged disk with excited cyclotron motion.This model gave a better agreement with the experimental data than the charged-point model. Control of ion kinetic energy in ICR spectrometry with respect to very low-energy collision-induced dissociation has been examined by Boering et aL2” Ions were continually accelerated and decelerated over a period of hundreds of milliseconds by repeatedly shifting the phase of the ratio frequency driving signal by 180” using an external electronic circuit. At low kinetic energies a succession of collisions which transferred small amounts of energy favoured the lowest energy fragmentation pathway and allowed ions with large activation energies to fragment at energies very close to threshold. Solutions have been reported for the frequency shift due to the induced image charges for both cylindrical and tetragonal ion traps as a function of ion axial and radial position.For a cubic trap the shift for an ICR orbital radius of one half the trap radius is -10p Hz for one ion. Thus a frequency shift in the ppm range can be expected for typical ICR experiments involving 1000-100 O00 ions at low m/z ratio (60-600).This has important implications for calibration.230 A new 20-dimensiona1 FT-ICR experiment stored-waveform ion modulation or SWIM 2-D-FT-ICR-MS/MS has been developed. Each row of the two-dimensional data array is obtained by the use of a single stored excitation waveform whose frequency-domain magnitude spectrum is a sinusoid the frequency of which changes from one row to the next.The conventional FT-ICR spectrum appears along the diagonal of the two-dimensional mass spectrum with off-diagonai peaks correspond- ing to ion-neutral reactions whose ionic components may be identified by horizontal and vertical projections to the diagonal spectrum. Fragmentation due for example to collision-induced dissociation results in a peak on only one side of the diagonal; bidirectional processes give peaks on both sides. All ion-molecule reactions can therefore be seen without any prior knowledge of the Self-assembly alkanethiol monolayers on gold films have been studied by laser desorption at 193 nm radiation.232 Adding sugars as comatrix elements permitted higher resolution than without sugar in MALDI-FT-ICR. Mass resolution of 6-10 OOO was obtained for melittin bovine insulin and bovine insulin 3chain which rose if ribose or fructose was added to the matrix.233 Capillary electrophoresis has been ”‘P.A. Limbach P. B. Grosshans and A.G. MarshalI And. Chem. 1993 65 135. 227 2.Guan S.A. Hofstadler and D.A. Laude Jr Anal. Chem. 1993 65 1588. ’’’ S. P. Chen and M.B. Comisarow Rapid Cornmun. Mass Spectrom. 1992,6 1. 229 K.A. Boering,J. Rotfe and J. I. Eirauman Rapid Cornmun. Mass Spectrom. 1992,5 303. 230 X. Xhang P.B. Grosshans and A.G. Marshall Int. J. Mass Spectrom. lon Processes 1993 125 33. 231 C. W. Ross 111 S. Guan P. B.Grosshans T.L. Ricca and A. G. Marshall J. Am. Chern.Soc. 1993,115 7854. 232 Y. Li J. Huang R.T. Mclver Jr and J.C. Hemmtnger J. Am. Chem. SOC. 1992 114 2428. 233 C. Koster,J.A. Castoro and C.L. Wilkins J. Am. Chem. SOC.,1992,114 7572. Physical Methods and Techniques -Part (ii) Mass Spectrometry 45 successfully interfaced with FT-ICR using an electrospray interface and a high speed cryopurnping arrangement. Initial results show that spectra with high sensitivity and excellent resolution (30ooCr50000)can be obtained every six FT-ICR has been used as a post-ionization technique for separation of electros-prayed protein mixtures.235 The relative order of trapping of the ions is determined by the application of potential to the skimmer cone and the ion velocity. The optimum trapping potential has been found to depend primarily on the m/z ratio within the electrospray envelope but also on protein-specific features including velocity slip in the expansion.10 Tandem Mass Spectrometry The combination of electrospray and FT-ICR provides possibilities for tandem mass spectrometry (MS/MS) and hence elucidation of molecular structure through collision-induced dissociation in the actual ion source (so called ‘nozzle dissociation’) in the case of very large ions (104Da).236 The difficulties inherent in the analysis of large multiply-charged proline-containing proteins have been addressed by Smith and coworkers.z37Low resolution tandem mass spectrometric data can be ambiguous due to the tendency of proline-containing proteins to form multiply-charged product ions. Collisional dissociation of proteins of up to 22 OOO Da ionized by ES was considered. Fragmentation due to cIeavage of the peptide bond near proline residues was usually dominant and this process was found to be the only dissociation pathway observed for many large proteins.Multiply-charged ions of an IgG class monoclonal antibody anti(human a,-acid glycoprotein) which has a weight of 149600 Da were produced by pneumatically assisted ES and then subjected to coilisionally activated dissociation with argon at collision energies of 5-12 keV in a triple-quadrupole mass spectrometer. The structurally significant light-chain fragment (23 720 f30 Da) was collisionally released. There is evidence that this took place near an energetic threshold and the energy required may well have come from the many collisions encountered by the anti body ions. Peptide and caesium iodide cluster ions decomposing to certain fragment ions following collision-induced decomposition have been shown to exhibit energy losses independent of transmission whilst parent ions of certain other fragments show strong dependence of energy loss upon transmission.These results have been interpreted in terms of energy redistributions taking place in single collisions by direct momentum transfer.239 MS/MS results for high mass ions (m/z 1000-2500) comparable to those obtained by four-sector instruments were obtained using a magnetic sector/quadrupole instru- men t . 40 Kenny and Orlando have reported MS/MS analysis of peptides at the femtomole 234 !LA. Hofstadler J.H. Wahl J.E. Btuce and R.D. Smith J. Am. Chem. Suc. 1993 115 6983. 235 S. A. Hofstadler S.C. Beu and D. A. Laude Jr Anal. Chem. 1993,65 312. ‘’‘ J,A. Loo J. P. Quinn S.I.Ryu K. D. Kent M.W. Senko and F. W. McLafferty Proc. Natl. Acad. Sci. U.S.A. 1992 89 286. 237 J. A. Loo C.G. Edmonds and R.D. Smith And. Chem. 1993,665 425. 238 R. Feng and Y.Konishi Anal. Chem. 1993 65 645. 239 C.D. Bradley and P.J.Derrick Org. Mass. Spectrom. 1993 28 390. 240 C. D. Bradley J. M. Curtis P. J. Derrick and B. Wright Anal. Chem. 1992,64 2628. 46 C.P. Ball and P.J. Derrick leveI using a four-sector instrument and array dete~tion.'~' Emptoying continu- ous-flow FAB the structures of several peptides (9W2000Da) at the 9OOfrnol to 5.8 pmol level were elucidated without interference from the background. Metabolites in a crude plasma extract from spontaneously hypertensive rats were identified without chromatographic separation by FAB MS/MS.242 The calcium-entry blocker AJ-2615 was detected and the structure elucidated.Compound-specific sequence ions were identified in the collision-induced dissociation spectra of the immonium ions of two isomeric hexaglycosyl~erarnides.~~~ Using standard EI the spectra had been too complex to distinguish the isomers from one another. Structure-specific collision- induced fragmentations of ceramides has been achieved by complexation of the analytes with alkali metal ions. Structures of individual components of complex mixtures could be detected with detection limits as low as 8 prn01.~~~ A number of different devices that can be used for surface-induced dissociation (SID) in tandem quadruple instruments have been evaluated on the basis of fragmentation of (C6H6)+*,[W(CO),]'* and (Me,N)+.Spectra obtained by in-line and 90" instruments were found to be similar.24s The overall efficiency for even-electron ions was higher than for odd-electron ions of similar structure. High average internal energies and narrow distributions of energies were said to be imparted to the parent ions in SID. SID of angiotensin I renin tetradecapeptide porcine pancreastatin fragment 3349 and ACTH fragment 1-17 has been observed in a four-sector MS/MS spec-tr~rneter.'~' Abundant fragment ions were seen facilitating determination of the amino acid sequences. SID has been applied to smal1 protonated peptides generated by The relative abundances of daughter ions were found to depend critically upon the energy of the ion-surface collision.At approximately 13eV collision energy the number of decomposition processes was maximized for the peptides studied. For the S1D process the kinetic energy distribution of the parent ions was said to be converted into a wider spread of centre-of-mass collision energies leading to a larger variety of decomposition processes compared to collision-induced dissociation. A comparison of the molecular and quasi-molecular ions of valinornycin formed using EI FAB field desorption (FD) and ES four-sector MS/MS has been made by Curtiset aLZ4'Large differences were observed between the FD and FA3 tandem mass spectra of [M + Na]" ions and between FD and EI spectra of M" ions.This was ascribed to formation of ions of different structures. A number of small peptides (500-1800amu) with various different masses were fragmented by SID in a tandem mass spectrometer as a comparison with collkional activation. The results allow the formulation of a model to explain the easy cleavage of 24i P. T. M. Kenny and R. Orlando And. Chem. 1992,64,957. 242 M. Kurono A. Itogawa K. Yoshida S. Narto P.Rudewicz and M. Kanai Biof. Moss Specrrorn. 1992.21 17. 243 J. M. Curtis P.J. Derrick J. Holgersson B. B. Samuehson and M. E. Breimer J. Am. Soc. Muss Spectrorn. 1992 3 353. 244 Q. Ann and J. Adams Anal. Chem. 1993,65 7. "'V.H. Wysocki,M. J. Ding J. L. Jones J. H. Callahan and F. L. King J. Am. Soc. Moss Spectiom. 1992,3 27.2*6 A. D. Wright D. Despeyroux K. R. Jennings S. Evans and A. Riddoch Urg. Mass. Spectrom. 1992,27 525. 247 R.B.Cole S. LeMeillour and J.C. Tabet Anal. Chem. 1992,64,365. ''' J. M.Curtis,C. D. Bradley P.J. Derrick and M. M. Shiei Org. Mass. Spectrom. 1992,27 502. Physical Methods and Techniques-Part (ii) Mass Spectrometry 47 the amide bond charge-remote backbone fragmentations and the influence of intramolecular hydrogen bonding.z49 Collision-induced dissociation was again com- pared with surface-induced dissociation (at 10eV) for peptides of mass 1300-1850. Only a small amount of the kinetic energy of the precursor ions is converted into internal energy for SID as the spectra resemble low energy collision-induced dissociation rather than the high energy spe~tra.’’~ A quadrupole ion trap storagelreflectron TOE; mass spectrometer has been developed as a detector for ES ionization.A continuous ES beam is converted into a pulsed beam for TOF measurement. Sensitivity in the low ferntomole region was demonstrated with small peptides. The spectrum can be acquired in less than one second.251*252 A reflectron TOF mass spectrometer for laser photodissociation has been described by Cornett et a1-253Mass selection was performed by pulsed deflection plates at the end of the initial drift section. Laser photodissociation of ions was effected at the turning point of the ion trajectory in the reflectron and the transit time through a second drift section defined the fragment masses (see also ref. 254). Scan laws havebeen derived for the detection of fragment ions produced by coIlisiona1 activation of a multiply-charged precursor in a floated collision cell of a four-sector tandem mass ~pectrometer.~~ ’ A review of collisional activation in MS/MS has been given by McL~ckey.~~~ A review of trace analysis of organics in mixtures has been made by Bieman~~~’ 11 Ion Trap The ion-trapping technique holds great promise as an inexpensive relatively high-performance mass spectrometer.The selectivity of methykne substitution in a low-pressure quadrupoie ion trap was elucidated by collisionally-activated dissociation.258 Dimethyl ether and ethylene the covalently bound adducts found at [M+ 451 and [M+ 411 respectively are direct + precursors to the methylene substitution product ions at [M+ 131+.It was discovered that at low helium pressures collisional-activated dissociation shows that the average internaI energy deposition is higher and sensitivity is not lost if a collisional cooling delay is added.259 Heavy target gases improved the trapping efficiency of caesium iodide clusters when added in small amounts to the helium buffer gas.260 Trapped ions were activated by applying a short DC voltage pulse to one end of a quadrupole ion-trap mass spectrometer.High internal energy deposition was obtained as evidenced by peak ratios in excess of 20 fur the m+ = 91 :m+ = 92 ions for the dissociation of the n-butylbenzene ion.26 249 A. L. McCorrnack A. Somogyi A.R. Dongre and V. H. Wysocki Anal. Chem.1993,65,2859. D. Despeyroux A. D. Wright and K. R. Jennings tnr. J. Mass Spectrom. ion Processes 1993 126 95. 25’ S. M.Michael B. M. Chien and D. M.Lubman Anal. Chem. 1993 65 2614. 252 S. M. Michael B. M. Chien and D. M. Lubman Rev. Sci. instrum. 1992,53 4277. 253 D.S. Cornett M. Peschke K.LaiHing P. Y. Cheng and K.F. Willey Rev. Sci. Inslrum. 1992,53,2177. 254 D. R. Jardine J. Morgan D. S. Alderdice and P.J. Derrick Org. Mass. Spectrom. 1992 27 1077. Is’ R. Orlando and R.K.Boyd,Urg. Mass. Spectrum. 1992 27 151. 256 S.A. Mchckey J. Am. SOC.Mass Spectrim. 1992 3,599. ’” K. Biemann Pure Appl. Chem. 1993,65 1021. ’” T. Donovan C.C. Liou and J. Brodbelt J. Am. SOC. Mass Spectrom. 1992,3 39. 259 C. Paradisi J.F.J. Todd P.Traldi and U. Vettori Org. Muss.Spectrom.1992 27 251. 260 K. L. Morand K. A. Cox and R.G. Cooks,Rapid Commun.Muss Spectrom. 1992,6 520. ”’ S.A. Lammert and R. G. Cooks Rapid Commun. Mass Spectrom. 1992 6 528. 48 C.P. Ball and P. J. Derrick The effect of the radial and axial dimensions on the Mathieu stability diagram (in terms of DC and RF voltages) has been discussed in relation to the stretched geometry employed in a commercial quadrupole ion-trap mass spectrometer.262 The effects of storing ions of different values of the stability parameters a and q were studied in a quadrupole ion trap using helium or argon A region was localized near the boundaries of the stability diagram where the ions experience an increase in their kinetic energy reflected by the occurrence of fragmentation due to collisional activation and a certain extefit of ion loss due to unstable trajectories.These effects known as boundary effects depend on the buffer gas and on q of the ions it is rep~rted.'~' Simultaneous data obtained from each of the two steps of a MS/MS experiment show that the collisional history of the ions before the isolation process can greatly influence the degree to which ions can survive isolation. The facility with which ions absorb energy from the field within the trap or whether the field is derived from the radiofrequency potential or a supplementary potential can determine the extent to which ions are retained in the field.265 The fullerenes C, and C, were found to be ionized by desorption from a liquid matrix upon bombardment by caesium ions of 7 KeV kinetic energy.266 The resulting radicaI cations when activated in the ion trap by collisions with Xe target gas undergo extensive dissociation by loss of multiple C2 units.Expressions for the ion-resonance ejection line shape have been derived incorporat- ing terms for ion-molecule collisions and variation with time of the resonance excitation frequency.267 The results show that for any non-zero scan rate there is an optimum collision damping value corresponding to a resolution maximum. Schwartz and Jardine discovered that the same techniques used for generation of high-resolution mass spectra on a quadrupole ion trap can be used for selection or storage of a very narrow mass window with nearly 100% efficiency.268 Resonant ion ejection in a quadrupole ion trap was used to obtain mass measurement accuracy of better than 0.015% on gramacidin SZ6'Traldi Catinella and Bortolini suggested that mass displacements seen in the ion-trap mass spectra of certain fluorinated benzene derivatives were due to an interaction with the permanent dipole moment of the ion within the radiofrequency field.270 It was found that at specific q values higher-order fieId effects caused a decrease in the intensity of chemical ionization reagent ions due to inefficient storage.These are found to occur continuously along iso-j? lines for fi2 = 1/3 and 2/3.27' McLuckey et al. found that random noise applied to the end caps of quadrupole ion traps was effective in inducing collisional activation of trapped ions independent of m/z ratio and number of ions.272 Efficiency was a factory of three less "'J.V. Johnson R. E. Pedder and R. A. Yost Rapid Commun. Mass Spectrom. 1992,6 760. 263 K. L. Morand S. H. Hoke 11 M. N. Eberlin G.Payne and R.G. Cooks,Urg. Mass. Spectrom. 1992,27 248. 264 C. Paradisi and P. Traldi Rapid Commun.Mass Spectrorn. 1993 7 690. ''' R. E. March M. R.Wier M. Tkaczyk F. A. Londry R,L. AIfred A. M.Franklin and J. F.J. Todd Urg. Mass.Spectrom. 1993 28 499. 256 H. F. Wu and 3. Brodbelt int. J. Mass Spectrorn. Ion Processes 1992 115 67. 2c7 D. E,Goeringer W. B. Whitten M.J. Ramsey S. A. McLuckey and G. L. Glish Anal. Chem. 1992,64 1434. J. C. Schwartz and I. Jardine Rapid Commun. Mass Spectrom. 1992 6 313. 269 J. D. Williams and R.G.Cooks Rapid Commun.Mass Spectrom. 1992 6 524. 270 P. Traldi S. Catinella and 0.Bortolini Urg. Mass. Spectrom. 1992 27 927. 271 D. M.Eades and R. A. Yost Rapid Commun. Mass Spectrom. 1992,5 573. 27f S.A. McLuckey D. E. Goeringer and G. L. Glish Anal. Chem. 1992,64 1455. Physical Methods and Techniques -Part (ii) Mass Spectrometry than for conventional methods and there is evidence for discrimination against low m/z product ions for multiply-charged biomolecules however. A quadrupole ion-trap mass spectrometer was used to examine internal energy deposition and fragmentation pathways of ionized pyrene and anthracene.”’ Through multiple collisional-activation steps large amounts of energy can be deposited and multiple-stage dissociation reactions are observed.High-energy pathways can also be accessed in single stage MS/MS experiments by introducing a small amount of xenon as a target gas with the helium buffer which also imparts a high dissociation efficiency. A capillary SFC instrument with direct on-column injection was connected to a quadrupole mass filter/ion trap by a custom buiIt interface.274 The ion source was a standard electron impact-chemical ionization and operated using conventional ion trap electronics. This enterprising system was characterized and optimized. A sample of 80 fmol of anthracene provided a molecular-ion peak with a signal-to-noise ratio of 20. The interfacing of particle beam analyses with ion traps has been performed The particle-beam interface was directly coupled with a quadrupole ion-trap mass spectrometer without the use of an external ion source and vaporization ofthc particle beam and ionization by electron impact are all accomplished in the ion trap.Lower limits of detection for pesticides were seen than for conventional particle-beam systems using quadrupole mass analysers although non-linear calibration curves seem to be the rule.27’ Quantitative analysis by ion-trapping was investigated by Strife and Simms when they used one gram plasma samples spiked with antiinflammatory drugs at levels of 1-100ng (with a standard at 50ng).276 Crude extracts of the sample were analysed using scan voltages combining radiofrequency (r.f.) and d.c. voltages and an ion-trap tandem mass spectrometer. Ion-trap chemical ionization performance has been improved by the application of a modified scan function for the rejection of undesired electron-ionization-like ions formed at the beginning of the ionization period.277 Desorption-ionization has been accomplished in a quadrupole ion trap by using a fibreoptic interface with Gramicidin C as the reagent.278 Trapping was found to be most efficient using a high gas pressure (21mtorr) a long storage delay (250 rns) prior to detection and a low radio-frequency trapping potential during the desorption pulse.Ion-molecule reactions were also observed during the experiments. A MALDI instrumentfor use with ion trap mass spectrometry has been developed. The laser beam and the sample are brought through holes in the ring electrode allowing the laser-desorbed ions to expand and fill the ion trap.Detection limits in the ferntornole range have been achieved for many small polypeptides such as bradykinin neuro- medim U-8 and leucine-enkephalin. However a loss of sensitivity was seen at m/z above 3000,279 273 B.D. Nourse K.A. Cox K.L. Morand and R.G. Cooks,1.Am. Chem. SOC. 1992,114,2010. 2 74 J. D. Pinkston T. E. Delaney K. L. Morand and R.G. Cooks,Anal. Chem. 1992,64,1571. ”’ B.L.Kleintop D. M. Fades and R. A. Yost Anal. Chem, 1993,65 1295. 276 R.J. Strife and J. R. Simms J. Am. SOC,Mass Spectrom. 1992,3,372. 277 T. Cairns K. S. Chiu E. Siegmund and M. Weber,Rapid Commun. Mass Spectrom. 1992,6,449. 278 A. McIntosh T. Donovan and J. Brodbelt Anal. Chern. 1992,64,2079. 279 D. M.Chambers D. E.Goeringer,S.A. McLuckey. and G.L. Glish Anal. Chern. 1993,65,14.

ISSN:0069-3030    

DOI:10.1039/OC9939000021

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

3 Theoretical Organic Chemistry By C.A. REYNOLDS Department of Chemistry and Siulogical Chemistry University of €sex Wivenhue Park Colchester C04 3SQ UK 1 Introduction Theoretical organic chemistry is a wide ranging topic; theoretical chemists approach this discipline from a number of diverse perspectives ranging from extremely accurate methods applied to small model systems through to methods applicable to large biological molecules where the aim is to seek insight into complex processes rather than to produce quantitative results. Fortunately the author of the review has been encouraged to be selective rather than exhaustive. Consequently the topics covered reflect the author's interests and have been grouped into three sections density functional theory (DFT) because the author believes this will have a tremendous impact on theoretical organic chemistry in the years to come (for the reasons outlined below); calculations involving solvation since although sohation is still largely neglected it is clearly important in organic chemistry; and transition structures because they are the key to understanding mechanism.To conclude a short section is appended at the end on neural networks since these represent just one of many new computational techniques which are beginning to be applied in interesting ways to Chemistry. Indeed one of the criteria for including articles for review is the author's perception of the future potential of the methods for use in application to organic chemistry. 2 Density Functional Theory In the opinion of the author density functional theory (DFT)' is poised to make a revolutionary contribution to theoretical organic chemistry.The reasons for this are that it is potentially exact,2 it scales very favourably with size (usually N3where N is the number of basis functions though there is currently much research on order N methods in quantum chemistry) and it has recently been shown to give very promising results (seeTable 1). Since the method may be unfamiliarto many readers the relevant features are discussed below followed by an overview of a selected proportion of the interesting results published in 1993. Background.-Within traditional molecular orbital (MO) methods where the total R.G.Parr and W. Yang 'Density Functional Theory ofAtoms and Molecules' Oxford University Press New York 1989.P. Hohenkrg and W. Kohn Phys. Reix B 1964 136 864. 51 C.A. Reynolds wavefunction 'B is constructed as a product (actually determinant) of N one-electron molecular orbitals # !P = t4rdr#,-#NI (11 the total energy of a molecule is composed ofone-electron terms (the kinetic energy and the electron-nucIear potential terms) and two-electron terms. The two-electron terms consist of the coulomb energy and the exchange energy. All of these terms involve integraIs over basis functions and the integrals are evaluated analyticaIIy. In addition accurate calculations require evaluation of the correlation energy which is not present in self-consistent field (SCF) MO calculations.Generally the correlation energy is evaluated by including excited states and so effectively the total wavefunction is now a linear combination of a large number of determinants similar to that on the right hand side of Equation (1). Such multi-determinant wavefunctions are essential for the accurate description of many chemical processes particularly dissociation and so they are also essential for a reliable description of transition states. It is the calculation of the correlation energy which render impossible accurate ab initio calculationsfor systems ofreal chemical interest because the calculations scale according to N5for the simplest approach [second order Maller-Plesset theory (MP2)] which does not even describe dissociation correctly and according to N7 for the more reliable approaches such as higher order M~rller-Plesset perturbation theory or coupled cluster calculations.In the light of this unfavourable scaling density functional theory possibly o@rs the only reliable alternative. The essentials of the method are given below. Density Functional Methods.-Within the local density approximation (LDA) the exchange energy is evaluated as follows J r EtDA= C dr~(r)~'~ where C is a constant and p is the electron density. The integral is now usually evaluated numerically over a grid. A key question when assessing DFT calculations is whether this integral has been evaluated accurately; a reasonable check is aIso to integrate p(r) over the grid which should give the total number of electrons in the molecule.Probably the most significant change came in 1988 when Becke proposed that the gradient of the density was also important in evaluating the exchange energy.3(Such methods involving Vp(r)are termed non-local or gradient methods.) ..2 where p is a constant and x = I Vp(r)l/p4/3.The correlation energy can be evaluated in a similar manner using local or non-local functionals. The non-local methods are usually denoted by a combination of letters to denote the combination of functionals for exchange and correlation; thus B-LY P denotes the Becke '88 exchange functional3 plus the Lee Yang and Patr correlational f~nctional;~ B-VWN denotes the Becke A.D. Becke Phys. Rev. A 1988 38 3098. C. Lee W. Yang and R.G. Pan Phys. Reu. B 1988,37,785;B.Miehlich A. Savin H. StolI and H. Preuss Chem. Phys. Lett. 1989 157,200. Theoretical Organic Chemistry exchange functional plus the Vosko Wilk and Nussair correlational f~nctional.~ There is currentIy much research into new functionals and we can certainly expect the current functionals to be superseded. A number of choices exist as to how the density is evaluated. The integrals in Equations (2) and (3) may be evaluated using any density and results show that the answers may not differ significantly whether the density is evaluated in a manner which is self consistent with equation (2) or (3)$ alternatively any other density such as an SCF density may be used. In chemical applications the density is usually constructed from atom-centred basis functions as in traditional molecular orbital methods though the resultant orbitals thus produced by the Kohn-Sham method may not have the same physicaI meaning.In studies ofmolecules interacting with surfaces it is common to construct the density from plane waves (see section on Carr-Parrinello methods). Model Studies on Small Molecules.-Since DFT is a reasonably new technique for chemists (but not for physicists who generally look at much larger energy differences) it has been important to estabiish the reliability of density functional theory in chemical problems. It is this area where significant and exciting progress has been made in the last twelve months. To date there have been few genuine application studies that have significantly enhanced our understanding of chemistry.However there have been many significant studies on model systems. Some studies have considered the performance of DFT in predicting molecular properties for a large number of molecules; understandably the most systematic study by Johnson et al.,came out of the Pople group.’ The general findings are for bond lengths the €3-LYP functional gives bond lengths which are too long by about 0.018 A -the error is comparable to that of Hartree-Fock methods but the sign of the error is reversed; for dipole moments the errors are similar to those of Hartree-Fock methods except that DFT has some success fur difficult molecules like CO and NO; atomization energies are extremely well predicted by both the B-LYP and B-VWN methods with a mean error close to zero; and harmonic frequencies are generally well produced with the errors generaIly less than those obtained using MP2 methods.Studies on bond breaking processes have also found that non-local DFT is valid for multideterminant problems,8 and this is a very significant observation (see also transition state references in Table 1). For energetics the majority of researchers find that density functional theory generally performs as well as MP2 (in the cases where MP2 is vaIid). This appears to be at odds with Johnson et who generaIly find it vastly superior. However as Johnson shows the errors in traditional approaches tend to be systematic whereas the errors in DFT methods tend to be random and this tends to account for why DFT performs simiiarly to MP2.Not all ofthe studies in Table 1are significant by themselves. However the weight of the evidence presented in this selection of papers is extremely strong particularly for those involving calculations of dissociation energies or transition structures. More- over given the volume of research into new functionals the preference for density functional theory over traditional approaches will grow and we wiil surely see DFT having a very profound influence on theoretical organic chemistry. Partly as a warning S. H. Vosko L. Wilk and M. Nusair Con. J. Phys. 1980 58 1200. C.T. Lee G. Fitzgerald and W.T. Yang J. Chem. Phys. 1993,98,2971. ’ B.G. Johnson P. M. W. Gill and J.A. Pople J. Chern. Phys. 1993 98 5612. C. W. Murray N.C.Handy and R. D. Amos 1.Chem. Phys. I993,98 7145. C.A. Reynolds some of the articles in Table 1 are based on local density functional theory which the table shows may give good results. However a closer look will show that reliable results often require non-local methods. (Needless to say the table does not show the cases where density functional theory performs badly.) Applications.-At this point it is helpful to review briefly two applications that illustrate the power of density functional methods. The first is a study ofthe isomers of N,H and illustrates how favourably the energy barriers connecting the various isomersofN,H calculated using non-local density functional theory compared to those calculated using high level ab initio methods such as G2 theory?*" The potential energy surface is illustrated in Figure 1 in which the relative energies given (in kcalmol-') are for Hartree-Fock; non-local DFT; G2 theory respectively.) 89;70;70 H -;49;50 /\ H H/N=N N=N H / H' N=N 6N=N H/N=N H 20;22;24 0;o;o 7;5$ Figure 1 The use of DFT to study organometaIlics is aptly illustrated by studies on H-H and C-H bond activation by the a-bond metathesis reaction (Scheme 11." The bond dissociation energies of the cornpIex have been caiculated to within 2&30 kJ mol -(4.5-7.5 kcal mold ') of experiment.The transition structures for the above reaction have been located and the activation energies are consistent with the experimentally observed rate constants thus the results are generally in line with experiment.Scheme I J. Andzelm C. Sosa and R.A. Eades,J. Chem. Phys. 19!?3,97,4664. B.J. Smith J. Phys. Chem. 1993 9,10513. *l T. Zieglcr E. Folga and A. Berces J. Am. Chem. Suc. 1993,115,536. Theoretical Organic Chemistry C z em me -I? me 0 L. emee em emmm mm - d c$ *+ 5P em Ii ‘C om me e w eeeeew C. A. Reynolds Finally it is appropriate to note that DFT methods are now available in the popular GAUSSIAN’2 and CADPAC13 traditional quantum chemical codes as well as from other commercial sources. Carr-Parridlo Methods.-Carr-ParrineIlo methods combine quantum mechanical methods with molecular dynamics. (The local density approximation is usually used along with pseudopotentials to represent the cure electrons and the basis set is typically constructed from plane-waves rather than atomic orbital-like basis functions.) The inherent advantage is that molecular dynamics can be performed without the need for crude force-fields containing parameters which may be far from ideal.In addition bond breaking processes can be followed. The potential of this method for studying reactions is tremendous. However to date there are a number of technical problems and applications have largely been applied to cluster chemistry and related problems. References 14 and 15 illustrate the method and show how it can be used in combination with simulated annealing to overcome the multiple minimum problem and determine the global minimum for molecular structures.Excited States.-The Hohenberg-Kohn theorem2 is in principle valid only for the ground state electron density so there is as yet no universally held justification for applying DFT methods to excited states despite much research in this area. However a number of authors for example Dual et have shown that DFT can yield meaningfuI results when applied to excited states. 3 Solvation Backgromd.-AIthough it is widely understood by organic chemists that solvent effects can have a dramatic effect on reactivity it is rather surprising that most theoreticai studies stiIl do not include the effects of solvation as a matter of course. There are a number of reasons for this. One is the lack of suitable software though this reason is rapidly becoming out of date.Another is that while solvation effects are indeed important the errors due to the limitations of semiempirical treatments the errors due to basis set size limitations and the errors due to inadequate treatment of electron correlation (see above) are all still the largest potential errors in any calculation. A third reason is the lack of realistic models for treating solvation since all the models are defective in one way or another despite much research in recent years. A find reason is that some methods particufarly those involving computer simulations require specialist skills different to those required for accurate gas-phase studies of potentia1 energy surfaces. One notable contribution towards providing readily available software for solvation ’’ ‘GAUSSIAN 92/DFT’ Gaussian Inc 4415 Fifth Avenue Pittsburgh PA 15213 USA.l3 R.D. Amos ‘CADPAC 5.1’ University Chemical Laboratories Lensfield Road Cambridge UK CB2 1EW. K. Laasonen M. Parrinello R. Car C.Y. Lee and D. Vanderbilt Chem. Phys. Lett. 1993,207,208. Is R.O. Jones J. Chem. Phys. 1993,99 1194. l6 C. Dual H.U. Gudel and J. Weber J. Chem. Phys. 1993,98 4023. Theoretical Organic Chemistry 57 studies is the AMSOL program,51 which is available through QCPE.52The authors of AMSOL Cramer and Truhlar have published an excellent review53 of solvation models and despite the title (‘Continuum solvation models classical and quantum mechanical implementations’) both empirical and explicit water simulation models are discussed in addition to Poisson-Boltzmann reaction-field methods and generalized Born methods which are discussed in some detail.The review also includes a comparison (with experiment) of the various methods for determining free energies of hydration. (Cramer and Truhlar’s own generalized Born method54 certainly does well in this cornparison). An excellent review of Poisson-Boltzmann methods55 has also been published in the last year. A particular advantage of this method is that it is applicable to large systems and can inctude ionic strength in the caIculations. TypicaI uses inctude calculating the molecular electrostatic potential around macromolecules and calculating pK shifts in enzymes but as yet there have been few applications to l7 L.A.Eriksson S. Lunell and R.J. Boyd J. Am. Chem. SOC. 1993 115 6896. la A. D. Becke J. Chem. Phys. 1993,98 5648. l9 A.D. Becke J. Chem. Phys. 1993,97,9173. 2o H. Chen M. Krasowski and G. Fitzgerald J. Chem. Phys. 1993 98 8710. 21 R. M. Dickson and A. D. Becke J. Chem. Phys. 1993,99 3898. 22 L. Goodwin and D.R. Salahub Phys. Rev. A 1993 47 R774. 23 D. P. Chong D. Papousek Y.T. Chen and P. Jensen J. Chem. Phys. 1993,98 1352. 24 M.S. Stave and J. 3.Nicholas J. Phys. Chem. 1993 97 9630. 25 E. Folga and T. Ziegler 1.Am. Chem. Soc. 1993 115 5169. 26 I. Papai J. Mink R. Fournier and D.R. Salahub .I.Phys. Chem. 1993 97 9986. ’’ K. 0.Christe W. W. Wilson D. A. Dixon S. I. Khan R. Bau,T. Metzenthin and R. Lu,~. Am. Chem.SOC. 1993 115 1836.28 K.O. Christe D. A. Dixon J. C. P. Sanders,G.J. SchrobiIgen and W. W. Wilson,J. Am. Chem.Soc. 1993 115 9461. 29 K. 0.Christe D. A. Dixon I. B. Goldberg C.J. Schack B. W. Walther J.T. Wang and F. WiIliams,J. Am. Chern. Soc. 1993 115 1129. 30 A. Berces and T. Ziegler J. Chem. Phys. 1993 98,4793. 31 C. W. Murray G.J. Laming N.C. Hamdy and R. D. Amos J. Phys. Chem. 1993 97 1868. 32 1.G. Guan P. Duffy J.T. Carter D. P. Chong K. C. Casida M. E. Casida and M. Wrinn J. Chem.Phys. 1993,98 4753. 33 M. M.Huhn R. D. Amos R. Kobayashi and N.C. Handy J. Chem. Phys. 1993,98 7107. ” D. P. Chong and C.Y. Ng J. Chem. Phys. 1993 98 759. 35 P. Duffy and D.P. Chong Org. Mass. Spec. 1993 28 321. 36 D. Heinernann and A. Rosen Theor. Chirn. Acta. 1993 85 249.37 f.Politzer 3. M. Serninario M.C. Concha and J.S. Murray Theor. Chirn. Acta. 1993 85 127. ’’ C.Sosa C. Lee G. Fitzgerald and R. A. Eades Chem. Phys. Lett. 1993,211 265. 39 P. FIeukiger J. Weber R. Chiarelli A. Rassat and Y. Ellinger Int. J. Quant. Chem. 1993 45 649. 40 A. Berces and T. Ziegler Chem. Phys. Lett. 1993,203 592. 41 D.P. Chong and A.V. Bree Chem. Phys. Lett. 1993 210 443. 42 C. Mijoule 2. Latajka and D. Borgis Chem. Phys. Lett. 1993 208 364. 43 C. Lee and D. VanderbiIt Chern. Phys. Lett. 1993 210 279. 44 A. Ghosh and J. AlrnIof Chem. Phys. Lett. 1993 213 519. 45 J. M. Seminario Chem. Phys. Lett. 1993 206 547. 46 S. M. Colwell C. W. Murray N. C. Handy and R. D. Amos Chem. Phys. Lett. 1993 210 261. 47 I.A. Topoi and S. K. Burt Chem. Phys.Letr. 1993 204 61 1. 48 K. Waizurni H. Masuda H. Einaga and N. Fukushima Chem. Lett. 1993 7 1145. 49 R. D. Amos C. W. Murray and N.C. Handy Chern. Phys. Lett. 1993 202 489. T. Ziegler E. Folga and A. Berces J. Am. Chem. Soc. 1993 115 636. 51 C.3. Cramer G.C. Lynch G.D. Hawkins D.G. Truhlar and D. A. Liotard AMSOL 4.0 QCPE 606 QCPE BulIetin 1993 13(4). 52 Quantum Chemistry Program Exchange Creative Arts Building 181 Indiana University Bloomington IN 47405 USA. 53 C.J. Crarner and D.G. Truhlar Reviews in Computational Chemistry in the press. 54 C.J. Cramer and D.G. Truhlar 1.Cornput.-Aided MoI. Des. 1992,6 629. 55 B. Honig K. Sharp and A.S. Yang J. Phys. Chem. 1993 97 1101. 58 C.A. Reynolds organic chemistry despite recent encouraging results referred to in the review.One recent application has been to non-natural DNA triplex-forming olig~nucleotides.~~ Computer Simuiation Methods.-References to computer simulation reviews and texts are given in reference 19. Free energy methods57 have yielded very high levels of agreement between calcdated and experimental free energies including free energies of hydrati~n.~~ The real advantage of these methods is the treatment of specific solvent molecules. Jorgensen has shown how these methods implemented within a Monte Carlo framework can be useful for characterizing the hydration patterns of molecules. In particular the solute-water hydrogen bonding patterns can be n~ted.~~-~' Such effects may be important in determining mechanistic effects and conformational preferences in solution.62An algorithm for calculating residence times at particular hydration sites has been presented and may be helpful for anaIysing such structural features particularly for biorn~lecules.~~ Combining Quantum MechanicaI Calculations with Computer Simulatiom-Com-puter simulations are of necessity based on molecular mechanics (but see above for references to Carr-Parrinello methods).They cannot in general therefore describe bond-breaking processes. However a number of studies have described the combined use of quantum chemical studies with free energy perturbation (FEP)methods.'' Such approaches have been used to study the mechanism ofcarbonic anhydrase (by studying the underlying elementary reaction^)^^*^^ and the Mentshutkin reaction.66 The effect of solvation in reference 65 is quite marked although the gas phase reaction is barrierless the barrier in solution is over 19kcalmol-' and is mainly due to desolvation effects.Reference 64actually describes the use of an empirical valence bond method but the results are compared to ab initio calculations. The main value of this particular study is probably in illustrating the catalytic effect of the environment. The solvent was found to have a marked effect on the energetics the structure of the transition state in the type I1 S,2 Mentshutkin reaction and the charge distribution in the transition structure demonstrating the value of combined quantum mechan- ical-molecular mechanical calculations. Combined calculations have also been applied to the torsional barrier in 71-ethylimidaz~le."~ Here it was found that the torsional barrier was raised in sdution by nearly 2 kcal mol-and that the position of the barrier moved.Attempts were made to rationalize the effects in terms of solute-solvent hydrogen bonds but the effects were considerably more complex than expected. TuutomericEquilibria. Tautomeric equilibria provide very popular test systems for the 'I3 V.Mohan Y. K. Cheng G.E. Marlow and B. M.Pettitt Eiopoiymers 1993-33,1317. " D. L. Beveridge and F.M. DiCapua Annu. Rev. Biophys. Biophys Chem. 1989 IS,431. 58 C.A. Reynolds P.M. King and W.G. Richards Mol. Phys. 1992,76 251. 59 W.L. Jorgensen and T.B Nguyen J. Comput. Chem. 1993 14 195. 6o H.A. Carlson T. B. Nguyen M.Orozco and W. L. Jorgensen J. Camput. Chem. 1993 14 1240. 61 P.I. Nagy G.J. Durant and D.A. Smith J. Am. Chem. Soc. 1993 115 2912. 62 P.I. Nagy W. J. Dunn G. Alagona arid C. Ghio J. Phys. Chem. 1993,!?7 4628. 63 A.E. Garcia and L. Stiller J. Cornput. Chem. 1993 14 1396. 15' J. Aqvist M. Fothergilt and A. Warshel J. Am. Chem. Soc. 1993 115,631. 65 Z. Peng and K.M. Men J. Am. Chem. Soc. 1993,115,9640. 66 J.L. Gao and X. F. Xia J. Am. Chem. SOC. 1993 115 9667. 13' D. R. Lowis J. W. Essex and W.G. Richards Molec. Sim. 1993 9 349. Theoretical Organic Chemistry reliability of sohation free energy calculations because of the chemical interest of the underlying problem; however the results are frequently ambiguous as they require solvation calculations to be combined with high-level quantum chemical calculations.Thus Burton et al. studied the tautomeric equilibria between the dihydroxy (l) monohydroxy-monoketo (2) and the diketo (3) forms of maleic hydrazide; they showed that both FEP methods and self-consistent-reaction field (SCRF)methods (see below) predict the monohydroxy-monoketo to be the most stable and that solvation stabilizes the diketo form but that the dihydroxyform is unlikely to be observed in agreement with experiment.68 In contrast however the same group showed that neither the FEP method nor the polarized continuum method (PCM),69 nor the SCRF method yield results that are totally adequate fur modelling the equilibria involving 3-hydroxypyrazole (4) and its tautomers f5)-(7) even though the errors were not large.70 The calculations do show that poIarization of the solute is important (which is not generally included in FEP methods).These two examples clearly show that great care is still required in applying these methods despite much recent progress. ComputationalCost.In contrast to many implementations of the SCRF methods FEP methods remain computationally very expensive though a particularly imaginative method for reducing the cost of FEP calculations is given in reference 71. However many drawbacks of the method remain and some are listed in reference 72. If CPU time is a real issue then the lower-level implementations of continuum methods remain more promising for small molecules; a real advantage of continuum methods is that the calculations are frequently much more easy to set up.Continuum Methods-The Kirkwood-Onsager result for the free energy of solvation in a medium of relative dielectric constant E of a dipole p centred in a sphere of radius 01 is given by Equation (4). N.A. Burton D.V. S. Green I. H. Hillier P. J. Taylor M. A. Vincent and S. Woodcock J. Chem. Soc. Perkin Trans. 2 1993 33 1. 69 S. Miertus E.Scrocco and J. Tornasi Chem. Phys. 1981,55 117. '* O.G. Parchment D.V.S. Green P.J. Taylor and I. H. Hillier J. Am. Chem. Soc. 1993 115 2352. 71 G. King and R.A. Barford J. Phys. Chem. 1993,97,8798. '2 C.A. Reynolds J. W. Essex and W. G. Richards Chem. Phys. Lett. 1992 199 257. 60 C.A. Reynolds The result includes polarization of the soIvent by the solute.Quantum mechanical reaction field methods are frequently based on this result through modification of the self-consistent field (SCF) equations and are termed self-consistent reaction-field (SCRF) methods. Limitations of this approach frequently include truncation of the multipole series at the dipok level; the use of a spherical forellipsoidal) cavity which is frequently unrealistic; the wavefunction Y is approximate and does not usually include electron correlation (it may even be semiempirical); and the results depend markedly on the choice of cavity radius cc. In recent work the quantum mechanical dipole approximation has been extended to higher muhipoles within arbitrarily shaped cavities.73 However the convergence of such methods with regard to the multipole series and size/shape of cavity has recently been q~estioned;~~ in this work a distributed multipole series has been used -this approach certainly dues need a molecular-shaped cavity.39 A number of studies have aiso extended the SCRF method beyond the SCF level to the Msller-Plesset second order level (MP2I7’ and to the configuration interaction (CI) level;76 while this latter approach like all continuum methods is generally considered to be unable to treat strong specific solvation effects such as hydrogen bonds it can treat excited states.An implementation of the pofarizible continuum method of Miertus et al. including electron correlation up to third order has also been proposed.77 However given the rather crude description of the molecular shape usually used (but not in the PCM approach) and noting that the choice of radius has a marked effect on the predicted AG value it is questionable whether the more accurate treatment of Ip yields more accurate free energies of solvation particularly given the other known errors in continuum methods.In defence of traditional SCRF methods Young et al. noted that the method gave resuits of comparable quality to those from molecular dynamics simulations when applied to tautorneric equilibria partition coefficients and amine basicity. However the continuum methods systematically overestimated the free energies of hydration though the errors tended to cancel upon taking differences. Moreover they also found that going beyond the dipole in the SCRFmethod did not increase the accuracy.Good agreement with experiment was also found by the same group in studies on the conformatiunal preferences of the alanine di~eptide.~’ Clearly the performance of these continuum methods like any other method depends on the problem to which it is applied. A good illustration of the use of the PCM method is given by Tunon et al. who have combined the PCM method with high level ab initio studies (up to MP4) to look at the difference in acid/base behaviour of a series of alcohols in both the gas phase and soiution. 73 V. Dillet D. Rinaldi J. G. Anguyan and J. L. Rivail Chem. Phys. Lett. 1993,202 18. ’‘ R. R. Pappalardo E. S. Marcos M. F. Ruiz-Lopez D. Rinaldi and J. L. Rivail J. Am. Chem. Sac. 1993 115 3722.7s J.G. Anguyan Int. J. Quant. Chem. 1993,47,469. ’‘ M.V. Basilevsky G. E. Chudinov D. V. Napolov and L. M. Tirnofeeva Chem. Phys. 1993 173,345. 77 F.J.O. klvalle and M. A. AguiIar 1.Mol. Struct. (THEOCHEM),1993,99 25. 78 P. Young D.V. S. Green I.H. Hillier and N. A. Burton Mot. Phys. 1993 80 503. 79 I.R. Gould and I.H. Hillier 1.Chem. Soc. Chem. Commun. 1993 951. I. Tunon E. Silla and J.L. Pascualahuir J. Am. Chem. Soc. 1993 115 2225. Theoreticat Organic Chemistry Semiempirical and Classical Implementations of Continuum Methods.-In terms of agreement with experiment in real applications semiempirical continuum methods have probably given results as reliable as their ab initio quantum mechanical counterparts. The use of INDO/S-CI for studying excited states and spectra is quite widespread; in combination with a continuum method it has given quite good predictions of solvatochromic shifts of organic molecules.Another semiempirical method formulated within the NDDO framework has given very encouraging results on excited states and again can predict solvatochromic shifts quite well. The particular advantages of this method8* are the inclusion of the dispersion energy (which is not included in most continuum methods) as well as the cavity energy and very fast computation of the molecular electrostatic potential on the surface;83 the dispersion energy calculations are relatively time-consuming but are essential to model correctly certain solvatochromic shifts. This latter method is again based on the poIarizabie continuurn method of Miertus et ~1.,~'which dues use realistic molecular cavity shapes.Rather than trying to increase the level of treatment of !P in the method the Tomasi group have shown that a classical implementation of the method using point charges (provided that they are potential-derived charges) can give quite good calculated solvation energies. This observation could be quite significant for studying macro- molecules where a full molecular dynamics or quantum mechanical treatment could be very expensive.84 (Pappalardo et aL8 have also modelled the solvatochromic shift for the n -,n* transition of acetone using an MCSCF implementation of a continuum model with an ellipsoidal cavity). Due to its implementation within MOPAC93,86 the new COSMO methods7 is IikeIy to become very popular.However apart from showing that the glycine zwitterion is more stable in aqueous solution than the neutral form and a very small number of comparisons with experimental values as yet there is little indication of its general reliability. Applications.-Efiect of Hydration on Cycloadditions. The (2 + 2) cycloaddition of t-butylcyanoketene (8) to phenylethene (9) (Scheme 2) was studied using a four-orbital four-electron CAS-MCSCF method using earlier studies as a guide. Scheme 2 The most favourable route was found to proceed via a biradical intermediate in which steric interactions between the three substituents are minimized despite the observation that this mechanism does not produce the most stable product.The effect 'I T. Fox and N. Rosch J. Mol. Struct. (THEOCHEM) 1992 95,279. 82 G. Rauhut T. Clark and T. Steinke J. Am. Chem. Soc. 1993 115 9174. 83 G. Rauhut and T. CLark J. Comput. Chem. 1993 14 503. '* R. Montagnani and J. Tomasi J. Mol. Struct. (THEOCHEM) 1993,98 131. 85 R. R.Pappatardo M. Reguero M.A. Rabb and M. Frish Chem. Phys. Lett. 1993,212 12. 86 J. J. P. Stewart MOPAC 93 QCPE Bull. 1993 13. A. Klamt and G. Schuurmann J. Chem. SOC.,Perkin Trans. 2 1993 799. 62 C.A. Reynolds ofmodelling hydration by a multipolar expansion (to order six) in an elIipsoidal cavity was found to enhance the gas phase product preference,88 -though convergence problems in the multipolar expansion were noted. Significantly the differential solvation energy corrections for such asynchronous pericycIic reactions are sufficiently large to have a marked effect on selectivity.Nucteophiiic Additions and the SupermoIecuk Approach to Sohation. The nucleophilic addition of ammonia to small molecules with activated double bonds such as acrolein has been calculated at the MP2 level with stationary points optimized at the HF/6-3lG* level. The purpose of these calculations was to gain some understanding of the possible biological effects of such reactions involving DNA. Hydration energies were caIculated using a polarizabk dielectric continuum. However the major reduction in the barrier height on solvation was found only when an explicit catalytic water molecule was included in the quantum mechanical treatment.89 Such a supermolecule approach is currently the only viable method of studying solvent- assisted mechanisms.However the calculation of hydration energies by the continuum method is probably not feasible except in the AMSOL method which is designed to treat explicit water molecufes consistently. Potential of Mean Force Calculations.-The free energy profile for the rotationaf isomerization of N,N-dimethylformamide has been determined using a combined quantum mechanical-molecular mechanical approach. The hybrid AM l/TIP?P model was used with the AM 1 energies scaled to reproduce high level ab initio results. The potential of mean field was determined by statistical perturbation theory implemented within a Monte Carlo frame~ork.’~ The difference in polarity between the ground state and the transition state emphasizes the desirability of inchding polarization effects in such calculations.4 Transition Structures The theme of the majority of the articles reviewed in this section is inclusion of reports of calculated transition structures. Calculated transition structures and their asso- ciated barrier heights offer from theory a unique contribution to the study of organic reactivity. A useful general review on the interplay between experiment and calculated transition structures is given by Williams:’ who remarks that the transition structure is frequently calculated more accurately than the energy barrier -as judged against very high level ab initio calculations. For this reason the reader may wish to review the work reported below in the light of the earlier comments on ab initio methods and density functional theory; these ideas on the difficulty of obtaining definitive energy barriers are superbly illustrated in the high-quality articles described in the next section.Diels-Alder Reactions.-The long running controversy as to whether DieIs-Alder reactions occur via concerted or other mechanisms continues. Li and Houk9’ have M.Reguero R.R. Pappalardo M. A. Robb and H.S. Rzepa J. Chem. SOC. Perkin Trans. 2 1993 1499. 89 L. Pardo R. Osman H. Weinstein and J.R. Rabinowitz J. Am. Chem. Soc. 1993 115 8253. 90 J.L. Gao. J. Am. Chem. Soc. 1993 115,2930. 91 I.H. Williams Chem. Soc. Rev. 1993,22,277. 92 Y. Li and K.N. Houk,J. Am.Chem. SOC. 1993 115 7478. Theoretical Organic Chemistry applied state-of-the-art calculations to this problem and come down very firmly along the lines of the generally (but still nut universalIy held) view that the process is indeed concerted for the reaction between butadiene (10)and ethylene (I 1)(Scheme 3). Their calculations on the reactants concerted transition state (TS) biradical TS and biradical intermediate for the reaction between butadiene and ethylene are sum-marized in Table 2. -L Buadical Scheme 3 The difference in energy of 5.8 kcal rno1-l between the concerted and stepwise transition structures calculated using the 3-21G basis set falls to 3.4 kcaI mol- when zero-point energies are taken into account. For the 6-3tG* basis set the difference falls even further to 0.5kcal mol-* ;thus when entropy is taken into account the biradical process is predicted to be more favourable.Since the CASSCF calculations include six electrons in six active orbitals a good representation was indeed given. However the MCSCF method overestimates the stability of biradical species. The more reliable quadratic CI results favour concerted pathways and the overall conclusion based on several pieces of evidence is given in the final column of the above table. As discussed elsewhere in this article it should be noted that sotvation may have a marked effect on these relative energies and also that substituents may affect the pathway for analogues of either reactant in this reaction. For butadiene dirnerization a concerted mechanism is probably preferred but the calculations inchding eight electrons in eight active orbitals are not sufficiently accurate to make such definitive statements.This particular controversy probably has a few more years to run! There have been fewer studies of hetero-Diels-Alder reactions. The same group has studied the reaction of ten dienophiles uia seventeen transition structures by assuming the reaction is concerted but not necessariIy synchrono~s.~~ The reactivity differences and stereochemical preferences are discussed on the basis of the geometries and relative energies of the transition structures. It was shown that the lone pair orbitals on the dienophiIes can exert a large destabilizing influence on the filled orbitals of the butadiene and that these lone-pair-n-electron interactions can have a large influence on stereoselectivities.In some cases it is found that solvation by dichloromethane modelled by the Onsager reaction field can actually stabilize the reactants more than the transition state despite the large dipole moment in the transition state. Likewise there have been relatively few studies ofinverse Diels-Alder reactions. An interesting cjairn to emerge from the reaction shown in Scheme 4 is that the regioselectivity of the reaction is controlled primarily by the (estimated) attractive 93 M.A. McCarrick Y.D. Wu,and K.N.Houk J. Org. Chem. 1993 I,3330. Table 2 Relative energies (kcal mol -of reactants transition structures and intermediates calculated and determined experimentally for the reaction of ethylene with butadiene (Scheme 3) CASSCF/ CASSCFj Molecples 3-216 6-31G* UQCISD(T) RQCISD(T) Expt.Conclusions React ants 0.0 0.0 0.0 0.0 0.0 Concerted TS 37.3 43.8 29.4 25.5 25.1 & 2 0 Biradical TS 43.1 45.7 39.2 35.7 5 Biradical intermediate 41.1 40.7 30.3 29.8 27.3 3 Theoretical Organic Chemistry 65 dispersion interactions between the phenyI rings of the reactants.94 Semiempirical and Hartree-Fock methods are nut able to take these factors into account (though molecular mechanics based transition state studies could -see below) and hence the treatment at the MP2 level was necessary to explain the experimental findings. P P + -+ H-CrC-Pb Scheme 4 An interesting AM 1semiempirical study (with limited configuration interaction) of the reaction between acrylonitrile (12)and allene (13) (Scheme5) has been undertaken to help to explain the origin of the kinetic isotope effect observed with gem-dide~terioallene.’~ It is concluded that the kinetic isotope effect is due to the slower rotation of the heavier CD group as it approaches the second transition structure in the stepwise biradical reaction.NC H D “I D Scheme 5 Other interesting cycloaddition studies are reported in references 96-100. Competition Between SN2and h2 Mechanisms-In a high level (MP2/6-3 IG*) study of the effect of methyl substitution on the energetics of S,2 sabstitution uersus E2 94 J. Cioslowski J. Sauer J. Hetzenegger,T. Karcher and T.Hierstetter,J.Am. Chem.SOC.,1993,115,1353 95 E.A. Halevi and M. Wolfsberg .I.Chem. SOC.Perkin Trans. 2 1993,1493. 96 D.A. Smith and C. W. UIrner J. Org. Chem. 1993,58,4118. ” R.Sustmann W. Sicking and R. Buisgen J. Org. Chem. 1993 58 82. 98 S. Yamabe S. Kawajiri T. Minato and T. Machiguchi J. Org. Chem. 1993,58 1122. 99 F. P.Cossio J. M. UgaIde X. Lopez,B. Lecea and C. Palomo J. Am. Chem. Soc. 1993,115,995. loo B.E.Thomas J. D. Evanseck and K.N. Houk J. Am. Chem. Soc. 1993,115,4165. C. A. Reynolds elimination in the reaction of F-with (CH,),CHCl or CH,CH2CH,C1 Gronert has shown101 that the syn transition state for E2 elimination adopts a synclinal rather than a syn periplanar geometry (see also reference 102). The conditions under which syn periplanar transition states would be expected are postulated to be unsubstituted systemsor systems with endothermic or marginally exothermic eliminations and hence late transition structures.The effect of methyl substitution upon the above energetics is discussed in terms of the balance between the stenc effect of the methyl group and its ability to spread charge in both the transition state and the initial ion-dipole complexes. Aspects of this problem have also been addressed above; see reference 103. Hynes and coworkers'D2 have presented an interesting observation :for the reaction (CH,),CX + (CH3)&*X-(X = C1 Br I) their calculations predict that solvent stabiIization for the ionization actually decreases with increasing solvent polarity and yet the actual free energy also decreases (ie.transition state ionic character and separation decrease) in complete contrast to conventional explanations. The calculations are based on a two-state valence-bond model and the aprotic solvents are modelled using a continuum method; the calculated activation free energies in all solvents agree to within 5 1.5 kcal mol- of experiment. Lee and coworkers'05 have studied the effects of substituents on the S,1 reactivities ofcationic benzyl and mono and disubstituted benzhydryl with neutral leaving groups. It is interesting to note that a number of excellent linear relationships have been found between the enthalpy of activation and the reaction enthalpy the length in the ground state of the bond being broken and change in the length of this bond as it goes to the transition state.Hybrid Molecular MechanicaI-Quantum Mechanical Models of the Transition State.-Fuli quantum mechanical determinations of transition state structures are now fairly commonplace but they are not always routine and can therefore be time consuming. One way to increase the applicability of transition-state modelling to real problems in organic synthesis is to model the transition state using molecular mechanics usually using the MM2 force-field. This approach has been very successful in rationalizing stereoselectivity. Recent examples of this approach include crotyl- borane addition to aldehydes,lo6 the aldol reaction of en01 b~rates,"~ and the synthesis of lor,2j3,25-trihydroxyvitaminD .lo8 Photochemistry.-In a study of the photochemistry of butadiene Olivucci et ~1.'~~ have shown that the traditional view that excitation from the ground 'A; state to the first excited state 2A',,is followed by decay from the avoided crossing region to the ground state and that the efficiency of the decay is determined by the gap between the ground state; the excited state potential needs to be replaced by a mechanism where the S.Gronert J. Am. Chem. Soc. 1993 115 452. lo' F. M. Bickelhaupt L.J. Dekoning and N. M. M. Nibbering J. Org. Chem. 1993 58 2436. Io3 F. M. Bickeihaupt E. J. Baerends,N. M.M. Nibbering and T. Ziegfer,J.Am. Chem.Soc. 1993,115,9160. Io4 J.R. Mathis H.J. Kim,and J.T.Hynes J. Am. Chem. Soc. 1993 115 8248. D. S.Chung C. K.Kim B.S. 'Lee and I. Lee Tetrahedron,1993,49 8359. lo6 A. Vulpetti M. Gardner C. Gennari A. Bernardi J. M. Goodman and 1. Paterson J. Org.Chem. 1993 58 1711. lo7 A. VuIpetti A. Bernardi C.Gennari J. M.Goodman and I. Paterson Tetrahedron,1993 49 685. Io8 T. Takahashi M. Nakazawa Y.Sakamoto and K. N. Houk Tetrahedron Lett. 1993,34,4075. Io9 M.Ulivucci I.N. Ragazos F. Bernardi and M.A. Robb,J. Am. Chem. SOC.,1993 115,3710. Theoretical Organic Chemistry funnel from the excited state to the ground state is actually a conical intersection. Since at the conical intersection the energy of the excited state and ground state are equal the processes are fuIly efficient. The criteria for locating conical intersections are discussed; the process involves a constrained optimization on the excited state surface.Rather than several avoided crossings giving different products a single conical intersection connecting the excited state to the ground state governs the formation of all products; the decay from the conical intersection to the ground state occurs within a single vibration. The work was based on hybrid molecular mechanics-valence bond calculations which allowed for the rapid calcuIation of energies over a grid of points. The hybrid calculations are however fully supported by MCSCF calculations with a 4-31G basis set. In a similar study using the MCSCF/4-31G method throughout PaImer et ai. have studied the minima transition structures and conical intersections on the So S, and S surface of benzene which includes the Kekule forms of benzene along with Dewar benzene benzvalene prismane and the bicyclopropenyl structure (Figure 2).A wonderfully complex set of stationary points and conical intersections are presented. For example on the S surface the only minimum is a D, structure anti-Kekule valence-bond isomer (8) connected to a prefulvene-like transition state (h); this is linked to a conical intersection which connects to the ground state. The mechanism for the photosensitized cycloaddition reaction of penta- 1,4-diene has been studied using the MP2/6-31G* method.'" The mechanism proceeds via an inter-system crossing followed by rearrangement on So. Minimum energy crossing points between T,and So were located and it was found that the preferred route involved the triplet cyclic intermediate crossing to So followed by internal rotation of the terminal methylene group; the latter change involved relatively minor changes in the skeletal structure.Tunnelling.-Calculation of the transition state geometry is not always sufficient for inferring the rate of reaction; dynamics calculations and tunnelling corrections may also be required. In an application on the 1,5-sigmatropic rearrangement in cis-penta-1,3-diene Liu et al. have shown that the potential energy surface for dynamics can be calculated 'on-the fly' (i.e.by direct dynamics) using the semiempirical molecular orbital program MOPAC."' The advantage of direct dynamics is that it avoids the analytical representation of the potential energy function; it is this fitting problem that has prevented the application of modern dynamics theory to interesting organic and biochemical reactions.The calculations were based on variational transition-state theory (because this reduces the dynamics to contributions from reasonably localized regions of configurational space) including multidimensional semiclassical tunneling corrections. They show that tunnelling only occurred in a small region of the saddle point and that tunnelling can indeed account for the strong temperature dependence observed in the experimental kinetic isotope effect as well as accounting for the magnitude of the kinetic isotope effect. Repeating the calculations without tunnelling leads to significant errors of about 6eu in the entropy of activation and of about 4kcalmol-' in the enthalpy of activation.Although there were I. J. Palmer I.N. Ragazos F. Bernardi M. Otivucci and M. A. Robb J. Am. Chem. Soc. 1993,115,673. 'I1 M. Ohsaku N. Koga and K. Morokuma J. Chem. Soc. Perkin Trans. 2 1993 71. Y.P.Liu G.C. Lynch T.N. Truong,D. H.Lu,D. G.TruhIar and B.C. Garrett 1.Am. Chem. Soc. 1993 115 240408. C. A. Reynolds Figure 2 (Reproduced with permission from J.Am. Chem.SOC.,1993,115,673.01993American Chemical Society) differences in the results obtained with the AM1 PM3 and MIND0/3 Hamiltonians all three gave essentially the same results. The proton shift from CD,H to CF has been followed in a similar manner," -except that here it was necessary to obtain AM1 parameters specific to this reaction because the predicted enthalpy of reaction was too large and this would have resulted in the calculated barrier being erroneously too asymmetric.(The parameters were fitted to both kinetic and thermodynamic data subject to the restriction that parameters did not change by more than loo/,.) 5 Neural Networks The use of theory to predict chemical reactivity with great reliability is a clear yet distant goal for many theoreticians. Intrinsic errors in many of the models still in use ensure that much work remains to be done. In some cases an expert chemist could '13 Y.P.Liu D. H. Lu,A. Gonzalezlafont D.G. Truhlar and B.C. Garrett J. Am. Chem. SOC.,1993,115 7806. Theoretical Organic Chemistry make more reliable predictions than theory.With this in mind artificial neural networks are being applied with increasing frequency to chemical problems. Thearticle by Simon et on the use of neutral networks to predict which bonds in aliphatic molecules will break preferentially is a good example that shows where quantum chemical calculations may not be the most powerful predictive tool. However the neural network is able to learn the relationship between a number of empirical physical chemical descriptors (inputs) and reactivity (output). Schematically the neural network usually has the foIlowing form show in Figure 3 (this particular network was used to determine one-electron electrode potentials at pH 7from semiempirica1 heats of formation and free energies of hydration ).I Output Layer Hidden Layer Input Layer Figure 3 The inputs are initially multiplied by a (random) weight.The sum of the weighted inputs is then passed through a transfer function at the nodes in the hidden layer the output of which is summed to give the output. If this total output is different to that desired the weights are adjusted. When a given set of weights reproduces the desired output fur a set of data the network may be considered to have learned the underlying relationship -assuming one exists. A full introduction (specific to chemistry) is given in the excellent review' l6 and textbook117 by Zupan and Gasteiger and in the review by Rouvray.' ' The range of chemical problems that can be tackled using neural networks is probably limited only by the imagination and the availability of data suitable fur training.Recent applications include the classification of inductive and resonance effects,' l9 the prediction of I3C NMR chemical shifts,120,121 QSGR,lz2 IR spectra 'IA V. Simon J. Gasteiger and J. Zupan J. Am. Chem. SOC. 1993 115 9148. J. J. Wolfe J. D. Wright C.A. Reynolds and A.C.G. Saunders Anti-Cancer Drug Design 1994,9 85. 'I6 J. Gasteiger J. Zupan Angew. Chem. Int. Ed. Engl. 1993,32 503. 'I7 J. Zupan and J. Gasteiger 'Neural Networks for Chemists' VCH Weinheim 1993. D.H. Rouvray Ckem. Br. 1993 29 495. 'Ip V. Kvasnicka S. Sklenak and J. Pospichat J. Am. Chern. SOC. 1993,115 1495. ''* J.P. Doucet A. Panaye E. Feuilleaubous and P. Ladd 1.Chem. In$ Cornput. Sci. 1993 33 320. G.M.J.West J. Chem. In$ Comp. Sci. 1993 33 577. A.C.G. Good,S.-S. So and W.G. Richards J. Med. Chem. 1993,36 433. C.A. Reynolds interpretati~n,'~~ and HPLC retention times. The protein structure predicti~n,'~~-~*~ neural network inputs may include descriptors calculated quantum mechanically. 6 Conclusions It is appropriate to apologize to the authors of the many excellent works that have nut been included in this review due to oversight restrictions on space or otherwise but which show that theoretical organic chemistry remains a very healthy branch of chemistry. Q.C. Vanest P.J. Schoenrnakers,J. R. M. Smits and W. P.M. Nijssen Vib.Spect. 1993 4 263. 12* B. Rost and C. Sander J. Mol. Biol. 232 584. 12' G. Schneider and P.Wrede Angew. Chem.Int. Ed. Engl. 1993,32,1141.

ISSN:0069-3030    

DOI:10.1039/OC9939000051

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (i) Pericyclic Reactions By N.G. RAMSDEN Glaxo Research and Deveiupment Limited Greenford Road Gmenfurd Middtesex UB6 OHE,LJK 1 Cydoadditioas The similarity index proposed recently as a quantitative measure of the extent of electron reorganization during chemical reactions allows discrimination between allowedand forbidden concerted processes. This is due to the difference in the extent of electron correlation between them It also allows a simple evaluation of the relative energies of concerted and non-concerted reaction paths. Several pericyclic reactions have been investigated for the variation in electron correlation during their course. The role of electron correlation is found to be most critical for high energy species along the reaction coordinate.2 The similarity approach to chemicaI reactivity has also been used to study substituent effects in pericyclic p hem is try.^ The use of transition state modelling with empirical force fields for reactions including the Diels-Alder reaction and Cope and Claisen rearrangements has hen re~iewed.~ Transition states for the concerted and stepwise Diels-Alder reaction and 12 + 21 dirnerizationof buta-1,3-diene have been located.On the basis of these the diradical transition state for the DieIs-Alder reaction of ethylene and butadiene appears to lie some 5 kcal mol- above the concerted synchronous transition state.5 Ab initio MO calculations have been used to study the reaction of cyclopentadiene with a variety of dienophiles.Endu cis transition states are favoured and the lack of selectivity with acrylonitrile has been explained. Good agreement is found between enthalpies of activation and reactivities derived both experimentally and at the MB3 leveL6 Kinetic measurements on the Diels-Alder reaction of (1) show that a good correlation between -log k and (EHOMOEL,,,)-exists.’ The Diels-Alder reactions of (2) with phenylacetylenes have been studied by MO calculations. At the HF/6-31G* level head-to-tail cycloadditions are favoured over head-to-head cycloadditions. This finding is in agreement with experimental data and provides the first evidence for R. Ponec J Chem. InJ Comput. Sci. 1993,33 505. ’R.Pons and M.Strad Collect. Czech. Chem. Convniin. 1993,58,1751. R. Ponec Coflect.Czech.Chem. Comun. 1993,58 11. A J.E. Eksterowicz and K.N.Houk Chem. Rev. 1993,93 2439. Y.Li and K.N.Houk J. Am. Chem. Soc. 1993 IIS 7478. ‘W.L. Jorgensen D. Lim and J.K. Blake J. Am. Chem. Soc. 1993,115 2936. ’ R. Sustmann and I. Siangouri-Feulner Chem. Ber. 1993,126. 1241. 71 N.G.Ramsden 11) (21 regioselectivity being controlled by Van de Waal's forces.8 Frontier orbitals along the intrinsic reaction co-ordinate of [4 + 21 and [8 + 21 cycloadditions for ethylene and thiabutadiene have been studied by MO calculations. Even if the orbital phase of the reactant does not give favourable FMO interaction it may be converted into the correct phase on route.g The thermal transannular Diels-Alder reaction of (3) has been studied. Experimental results are in agreement with those predicted by theory.'* In the aminium salt catalysed reaction a diene cation-radical reacts with a neutral ketene in a [4 + 21 cycloaddition (Scheme l)." The influence of phenyl n electrons Scheme 1 during cycloaddition reactions of endo-3,3-diphenyltricyclo[3.2.1.02*4Joct-6-enehas been investigated.Diels-Alder reactions that are accelerated by increasing the electrophilic nature of the medium are accelerated by metal perchlorates in order of charge :radius ratio is. Mg2 > Ba2+ > Li > Na' .This is presumably due to the effect of the cation on the electrophilic nature of the rnedium.13 J. Cioslowski J. Sauer J. Hertzenegger,T. Karcher,and T. Hierstetter,J. Am.Chem. Soc. 1993,115,1353. S.Yamabe S.Kawajiri T.Minato and T. Machiguchi J. Org. Chem. 1993,58 1122. lo A. Ndibwami S. Lamothe P. Souay S. Goldstein and P. Deslongchamps Can. J. Chem. 1993,71,714. R. M.Giuliano A. D. Jordan A. Gaufhier and K. Haogsteen J. Org. Chem. I993,58,4979. M. Peeran J.W. Wilt R. Subrarnanian and D.S. Crumrine J. Org. Chem. I993,58 202. l3 A.Cassoschi C.Desimoni G. Faita A.G. Invernizzi S. Lanati and P.Righetti J. Am. Chem.Soc. 1993 115,8002. Reaction Mechanisms -Part (i) Pericyclic Reactions (4) X=CH20r0 (5)X=CH,orO A dienophile will add to the face opposite the methoxy group in both (4)and (5)due to both the diene conformation and secondary orbital interactions in the transition state.14A procedure for the conversion of endo (6)to exo (7)adductsin the Diels-Alder reaction has been determined (Scheme 2).The high em selectivity was investigated by Scheme 2 AM 1 transition state calculations.' A mechanistically interesting and useful reversal in the facial selectivityof the Diels-Alder reaction has been achieved (Scheme 3).16 The Scheme 3 #?-sulfinyl dienophile (8) has been shown to react with cyclopentadiene with a very high degree of diastereoselectivity.' The LUMO diene controlled [4+ 2) cycloaddition of azaazulenes with tetrazines has been described.I8 Fischer carbenes (9) undergo Diels-Alder reactions with comparable stereoselectivity to the Lewis acid catalysed reaction of the corresponding methyl ester. This makes them useful synthons in cases where the diene is intolerant of Lewis acids.N-arylcycIohepta-2,4,6-triene-1-imines react with benzonitrile oxirnes I4 M. Schrnittel and H. Van Seggern J. Am. Chem. SOC. 1993,115 2165. P.P. M. DoI A. J. H. Klunder and B. Zwannenberg Tetrahedron Lett. 1993 34 3181. H. J. Liu and Y. Hai Tetrahedron Lett. 1993 34,423. l7 T.K. Yang S. M.Hung C.Z. Chen Y. Jiang and A. Q. Mi Youjji Huaxue 1993 13 183. '* G. Frenzen W. Maisa U. Reirnes and G. Seitz Chem. Ber. 1993 125 441. l9 W.D. Wukff and T. S. Powers J. Org. Chem. 1993,58 2381. N.G. Ramsden via [4 + 21 cycloadditions.A Hammett p-value of 0.99 suggests nucleophilic attack of the imines to the nitrile oxides.20 (q6-Cyclohepta-I ,3,5-triene)tricarbonylchromium(o)undergoes a thermal [6 + 41 cycloaddition with both electron-rich and electron-poor butadienes to give the endo product.The reaction between the chirally enriched allene (10) and the perhaloalkene (11)has been studied both experimentally and by molecular modelling. Results suggest that (12)is formed by one continuous minimum energy pathway whilst (13)is formed from two competing pathways. The two stereoisomers of (13) have opposite absolute configurations and thus no chirality transfer is seen from (10) to (13).’* The reaction of fluorine and ethylene has been studied at the MP2/5-31*GleveLZ3 Fluorine approaches the ethylene doubIe bond vertically to form a perpendicular complex as the intermediate. This then rearranges to a rhombic-type complex as a transition state to give the finaf syn product. Cycloadditions between ketenes and cyclopentadiene have been studied by a semiempirical AM1 method.Ketene and methyl ketene react via a concerted but nun-synchronous twisted transition state with a small degree of charge transfer from the cyclopentadiene to the ketene. Chlorornethyl ketene however reacts in a stepwise manner.24 Acetylenic links can act as antarafacial components in [2 + 21 processes.25 N-Methylhex-3-yn-1-aminewill react in a nominal [2 + 2 + 2 + 2J Mobius process. Evidence for the concertedness of this reaction has been discussed. Silenes undergo L2 + 41 and [2 + 21 cycloadditions with imines.26 The [2 + 41 ’* K Ito K. Saito and K. Takahashi Heterocycles 1993 36 21. 21 J.H. Rigby H. S. Ateeq N. R,Charles S. V. Cuisiat M.D. Ferguson J.A. Henshilwood A.C.Krueger C.O. Ogbu K. M. Short and M. J. J. Heeg J. Am. Chem. Soc. 1993,115 I382. ” D.J. Pasto and J. Brophy J. Phys. Org. Chem. 1993,6 95. 23 T. Iwaoka C. Kaneko A. Shigiwara and H. Ichikawa J. Phys. Org. Chem. 1993,6 195. 24 J. Jiang D. Fang and X. Fu Gaodeng Xuexiao Huuxue Xuebuo 1993,14 696. Is A. Viola J. J. Collins N. FiIipp and J. S. Locke J. Org. Chem. 1993 58,5067. 26 A.G. Brook W. J. Chatterton and R. Kimarathasan Organometallics 1993 12 3666. Reaction Mechanisms -Part (i) Pericyclic Reactions adducts generally rearrange to [2 + 23 cycloadducts and these silazetidines decompose by a variety of mechanisms. Computations suggest a multistep diradical mechanism for the head-to-tail cycloaddition of two ~ilaethylenes.~’ Polarization of the double bond in silenes does not Iead to a concerted mechanism.The energy surface is similar to that of the ethylenexthylene reaction but both the activation energy and the energy of the diradical are much lower. The cycloaddition of tetrafluoroethylene and dicyclopen- tadiene is first order in dicyclopentadiene and second order in tetrafluoroethylene.28 The activation energy is 118.56kcal mol- Oxazolium-5-oxide(14)cycloadds to I ,2-dicyanocyclobutene(15) to give the imino acid (16) and the dihydroazepine (17).29 AM1 calculations have been used to rationalize the observed product stereochemistry and evaluate possible reaction mechanisms. The effect of solvent and substituents on the 12 + 21 cycloaddition of t-butyI- cyanoketene and styrene has been studied using a CAS-MCSCF method.The reaction proceeds uia a diradical in which steric interactions are minimized. However this minimization leads to a product with cis stere~chernistry.~’ New models for the [2 + 21 Staudinger reaction have been discussed.31 Simple feed-forward three layer neural networks have been used to classify and predict the regioselectivity of 1,s-dipolar cycIoadditions.32 A quantitative analysis of the transition states and energy barriers of the syn and anti cycloadditionsof norbornene and cis-3,4-dichlorocyclobu tene with formonitrile oxime has investigated the role of many factors involved in facial ~electivity.~~ Further studies have allowed the development of a conceptual framework involving repulsion delocalization and def~rrnation.~~ This has provided a detailed account of the geometry and energy differences between the syn and anti transition states.The cyclization of imine oxides has been studied. In the reaction of (19) with the furanone (18)the major product is derived from an em transition state.35 Exo adducts are also the major products from reactions of (20).36With furanones the stereochemistry ofthe products is cis due to an interaction between the nitrogen lone pair and the carbonyl group. When this interaction is not present for example in the dihydrofurans trans products begin to predominate. ’’ F. ktnardi A. Bottoni M. Olivucci M. A. Robb and A. Venturni J. Am. Chem. Soc. 1993 115 3322. ’’ N.B. Christova S.D. Pavlova and G. K. Kostov Kinet.Cutal. Lett. 1993 49 393. ’’ C.A. Matyanoff and I. J. Turchi Heterocycles 1993 35 649. ’’ M. Reguero R.R. Pappalarda M.A. Robb and H.S. Rzepa f. Chem. SOC.,Perkin Trans. 2 1993 1499. 31 F.P. Cossio 8. ha C. Cuevas A. Mieglo and C. Palomo An. Quim. 1993 89 119. 32 S. Sklenak V. Kvasnicka and J. Pospical Actu Gem. Hung. 1993,130 103. ’’ A. Rastelli M. Bagatti A. Ori R. Gandolfi and M. Burdisso 3. Chem. Soc. Farday Trans. 1993,89,29. ” A. Rastelli M. Bagatti and R. Gandolfi J. Chem. Soc. Faradey Truns. 1993 89 3913. ’’ D. Aionso-Peramau P. de March M.Figuerdo J. Font and A. Seria Tetrahedron,1993 49 4267. 36 P. Cid P.de March M.Figuerdo J. Font,S. Milan A. Soria and A. VirgiIi Tetrahedron 1993,454 3857. N. G.Ramsden I Q dj5O H 0- (19) DiastereoseIectivity in nitrile oxide additions to OppoIzer’s chiral suItarns cannot be explained solely by bulky groups shidding faces of the alkene.37 Transition states were investigated by PM3 methods and the origin ofthe selectivity appears to be a repulsion between the dipolar oxygen and the sultam oxygens.This is supported by the fact that selectivity is lost in the corresponding isothiazolidines. The work supports Hehre’s claim that electrostatic effects are a general determinant of facial selectivity. 2-Ethoxy and 2-ethylthio-l-azetidines(21 undergo 1,3-dipolar cycloadditions with nitrile oxides and nitrile ylids to give stable products. With nitribmines 1,2,4-triazoles (22) are unexpectedly produced.38 Benzonitrile oxides undergo 1,3-~ycloaddition reactions to give 1,2,4-oxadiazoles as the major products.IsoxazoIesand 4,5-dihydroxazoles are also produced. The kinetics of all these reactions have been determined and substituent and solvent effects on product distribution are discussed.39 The regioselectivity of the intramolecular reaction of N-4-methylpent-4-enyl nitrones has been investigated by AM1 MO methods and transition state theory. The difference in selectivity between the E and 2 isomers is enhanced by the effect on the relative activation entropies caused by introduction of the methyl group.40 The reaction of mesoionic 1,3-dithioliurn-4-oate (23) with phenyl isocyanate is not a 37 K. S. Kim,B. H. Kim W. M. Park S.J. Cho and B. J.’Mihn J. Am. Chem. SOC. 1993 115,7472. 38 K.Hemming A. B. N.Luheshi A.D. Redhouse R.K. Smalley,J. R.Thompson P.D. KenneweIl and R. Westwood Tetrahedron. 1993 49 4383. 39 P. Beltrane E. Cadoni C. Floris and G. Gelli Tetrahedron. 1993,49 7001. *O S. Ma and X. Fu Hauxue Xuebao. 1993,51,496. Reaction Mechanisms -Part (i) Pericyclic Reactions 1,3-dipolar cycloaddition as the product is an azetidinone. The phenyl isocyanate reacts with the open ketene isomer (24)of the mesoionic compound.41 The existence of Ar a free-resonant unstabilized azomethine ylid in a 1,3-dipolar cycloaddition has been demonstrated by 3C labelling.42 The cycloaddition of phenylsulfonyl allenes with diazomethane has been studied.43 The product pyrazolines undergo a variety of rnechanisticalIy interesting transformations. 2 Sigmatropic Rearrangements Chiral Lewis acids derived from binaphthol and diisoprupyltitaniurn dichloride catalyse the ene reaction of glyoxylate esters with silyl enol ethers rather than a Mukaiyama aldol reaction.44 Syn diastereoselectivity is very high with either isomer of the silyl enol ether and this can be explained by consideration of transition state geometries.A mechanistic pathway to explain the observed asymmetric induction during the Lewis acid catalysed ene reaction of (25)has been presented.45 The reaction XP A CN A CN (225) of enarnines with ethyf propiolate has been explained as an ene-addition reaction (Scheme 4).46Alloxan (26) and 1,3-dimethyIalloxan (27) undergo ready ene reactions at the centraI CU.47The stereoseiectivity of both reactions is determined by steric factors.The transition states for the ene reaction between propene and formaldehyde imine have been located by ab inibio MO calculation^.^^ The endo transition state is lower in energy when C-C bond formation occurs and the exo transition state is lower in energy when C-N bond formation occurs. This is due to interactions between the nitrogen lone pair and the central carbon atom of the ene. M. Bssaibis A. Robert and A. SouiU J. Chem. Soc. Chem. Comrnun. 1993 998. 42 J.M. Bentley D.M. Smith H.J. Wadsworth and C.L. Willis J. Chem. Res. (S) 1993 240. 43 A. Padwa M.A. Filipkowski D. N. Kline S.S. Murphree and P. E. Yeske,J. Org. Chem. 1993,58,2061. 44 K. Mikami and S. Matsukawa J. Am. Chem. Soc. 1993 115 7039. 4s K.Hiroi and M. Umemura Tetrahedron.,1993,49 1831 46 Z. Huang and M.Wang 3. Chem. Soc. Perkin Trans. 1 1993 1085. 4’ G. B. Gill and M. S. Hidris Tetrahedron. 1993 49 219. ‘* B. E. Thomas TV and K.N. Houk J. Am. Chem. SOC. 1993 115 790. N.G. Ramsden XOPh ““a XOPh U U U 0 (26) R=H (27) R= Me Scheme 4 Terminal fluorine atoms exert a significant inhibitory steric effect on both disrotatory eIectrocyclic closures of hexa- 1,3,5-trienes and Cope rearrangement^.^' Cope rearrangements of perfluorodienes proceed via a 1,4-cydohexyl diradical in contrast to the concerted rearrangement of non-fluorinated dienes.” Mass spectra of 2,s-diphenylhexa- 1,Sdienes have provided evidence for a cation-radical Cope rear-rangement in the gas phase.The reaction directionality is different to that for the thermal process.’ Activation entropies and energies have been calculated for the competing C-C cleavage and Cope rearrangement of (28).52 The stereoselectivity of the thio-Claisen rearrangement of S-crotyl-a-hydroxy ketene dithioacetals (29) is determined by the classical internal control obtained with a [3,3] sigmatropic shift.53 External control also exists based on the stereochemistry of the S-crotyi doubIe bond. The sohent effect on the retro-Claisen reaction has been studied and the rate constants found to be a linear function of Reichardt’s E,f30) solvent polarity This suggests that like the forward reaction the retro-Claisen is concerted with partial charge separation in the transiton state.An investigation of the migratory tendencies of several groups when undergoing a [I ,5] sigmatropic shift suggests that both good conjugative electron-withdrawing ability and the availability of a low-energy vacant orbital lead to good migratory ability.” However steric conformational and secondary orbital interaction effects can mask these. Further evidence is provided for the concerted nature of the reaction. Activation for a [l,5] hydride transfer and cycloaddition have been determined.56 A diradical with little ionic character is generated on themolysis of bicycloC2.1 .O]pen- ‘’W. R. Dolbier Jr and K. W. Palmer J. Am. Chem. Soc. 1993 115,9349. 50 N. Jing and D. M. Lemaf J. Am. Chem. SOC. 1993 115 8481. s1 H. Ikeda T.Takasaki Y. Takahashi and T.Miyashi J.Chem. SOC.,Chem. Commun. 1993,367. ’’ C. Herberg H. D. Beckhaus T.Koertvelyesi and C.Ruechardt Chem. Ber. 1993 126 117. ’’ P. Baslim and S. Perrio Tetrahedron 1993 49 3131. 54 G. Desimoni G. Faita S. Gratti Comini P. P. Righetti and G. Tacconi Tetrahedron 1993,49 2093. 55 D. W.Jones and R. J. Morrnan J. Chem. SOC.,ferkin Trans. I 1993,681. 56 T. H. Petersen and 8.K,Carpenter J. Am Chem. Soc. 1993 115 5466. Reaction Mechanisms -Part (i) Pericyclic Reactions tane derivatives. The energetics of [I ,5] sigmatropic hydrogen shifts in cyclopen- tadiene pyrrole and phosphole and have been determined from ab initio calcuIa-ti on^.'^ Activation enthaIpies have been used to explain the reactions of these heterocycles. The kinetic isotope effect for the [131 sigmatropic rearrangement of cis-penta-l,3-dienes has been studied by a direct dynamics method.” The contribution to the shifts by and the nature of tunnelling effects have been discussed.Kinetic studies on the rearrangement of tetraphenylcyclopentadienes(30)suggest that they occur by [1,3] and [1,5] sigmatropic shifts.” Ab initiu MO calculations show that the Ph Ph Ph Ph6,. Ph (30) suprafacial[1,3] hydrogen shift of H,CHC=PH to H,C=CHPH and the degenerate H,PCH=PH to HP=CHPH shift exist and compete favourably with the an- tarafacial process.60 A [5,5] sigmatropic shift has been observed in the thermal rearrangement of (3 A new route to 3-aminodeoxystatine derivatives employing a [3,3] sigmatropic shift under paIladiurn catalysis has been demonstrated.62 The mechanism and selectivity of the electrocyclization of (32) have been inves- tigated.63 The electrocyclic ring opening of (33) has been discussed.The calculated Gibb’s Free Energies are in agreement with the equilibrium determined experimen- tally.64 The electrocyclic reactions of syn and anti bishornoaromatic heterocycles (34) ’’ S. Bachrach J. Org. Chem. 1993,58 5414. Y.P.Liu C.C. Lyngh T. N. Truong D. H. Liu D.G. Truhlar and B.C. Garrett J. Am. Chem.Soc. 1993 115 2408. s9 P. Sebek,P. Sedmera S. Bohm and J. Kuthan Collect. Czech. Chem. Commun. 1993.58 882. M.T. Nguyen L.Landuyt and L.G. Vanquickenborne. Chem. Phys. Lett. 1993,212 543. 61 K. Hafner H.J.Linder W. Luo K. P. Meinhard! and T. Zink Pure Appf. Chem.1993,65 17. A.M. Doherty B.E. Kornberg and M.D. Rielly J. Org. Chern. 1993,58 795. 63 M. Leclaire S. Bathnagar and J.Y.Lallemand Bull. SOC. Chirn. Fr. 1993 130 310. I. J. Turchi J. B. Press J. J-McNally M. P. Bonner and K.L. Sorgi J. Org. Chem. 1993,58,4529. N. G. Ramsden (34) x =o,s have been studied e~perimentalIy.~~ The electrocyclic ring opening of singlet oxirane has been studied and it is suggested that the stereochemistry of oxirane cycloadditions is due to competition between a conrotatory asynchronous process and a single methylene rotation process.66 AM1 MO calculations of the reaction path for ring expansion of the cycIobutylideny1 carbene suggest that the process produces a lumomer of cyclopentyne rather than cyclopentyne Products obtained from subsequent cydoadditions are consistent with this.Further calculations on the reaction path of these [2 + 21 and [4 + 23 cycloadditions of the lumomer show concertedness for the former process and stepwise for the latter. Results are consistent with Dewar's theory of orbital isomerization.68 3 Other Reactions A [2,3] Wittig rearrangement via a concerted five-ring transition state has been accomplished overcoming a severe six-ring deformation barrier.69 Interactions of buta-1,3-diene with oxygen on a silver surface have been studied by extended Hiickei tight binding calculation^.^^ Interaction of a terminal carbon of the diene with surface oxygen gives an intemediate which undergoes preferential 1,4 ring closure to a tetrahydrofuran.Phenylchlorocarbene reacts with [I. l.l]propellane to give (35). There is nu evidence for a diradical intermediate as is found for the corresponding reaction of diphenyl~arbene.~' " T.Gob,S. Hammes and F.G. Klaerner Chem. Ber. 1993 126 485. 66 Y.Yamaguchi H. F. Schaefer 111 and I.L. Alberts J. Am. Chem. SOC. 1993,115 5790. 67 J.C. Gilbert and S.Kirschner Tetrahedron Lett. 1993 34,599. '* 3. C. Gilbert and S.Kirscbner TetrahedronLett. 1993 34,603. 69 Z. You and M. Koreeda Tetrahedron Lett. 1993 34>2597. 70 B. Schioett and K. A. Jorgensen J. Phys. Chem. 1993,W 10738. '' J.C. Scaiano and P. F. McGarry Tetrahedron Lett. 1993 34 1243.

ISSN:0069-3030    

DOI:10.1039/OC9939000071

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (ii) Free-radical Reactions By S. CADDICK School of Chemistry and Molecular Sciences University of Sussex Falmer Brighton BNI SQJ UK 1 Introduction Research into the development offree-radical processes continues to attract significant interest and many notable advances have been published in the 1993 literature. This year’s highlights will focus on four general themes but there will inevitabIy be some overlap between the areas initiators promoters and mediators; intramolecular reactions; intermolecular reactions; applications of radical processes to synthetic and bioIogica1 chemistry. 2 Initiators Promoters and Mediators Fraser-Reid’ and coworkers have demonstrated the utility of di-t-butylhyponitrite (DBH) as a convenient reagent for the generation of carbon-centred radicals.Many synthetically useful applications have been illustrated; the hydroxymethylation of enone (1) is a particularly good example. MeOH. DBH Reflux. 1Sh. 77% OEt I OEt (1) (2) Given the popularity of the SnBu,H/AIBN system new methods for the generation of tributyltin radicals are of considerable interest. Previous work had examined the utility of bis(trimethy1stannyl)benzopinacolatefor the generation of trimethylstannyl radicals. Two recent reports2v3 demonstrate the ability of bis(tri-n-butylstann-y1)benzopinacolate (3) to generate tributyltin radicals and benzophenone under thermal conditions. Silicon reagents continue to attract interest as promoters; Chatgilialoglu’s group ’ B.Venkateswara Rao J. B. Chan N. Moskowitz and B. Fraser-Reid Bull. SOC.Chim. Fr. 1993 130,428. D.J. Hart R. Krishnamurthy L. M. Pook,and F.L. Seely Tetrahedron Left. 1993 34,7819. M.J. Tomaszewski and J. Warkentin J. Chem. SOC.,Chem. Commun. 1993 1407. 81 S. Caddick has in an interesting report demonstrated that care must be taken when choosing initiators for these reagents. Thus reduction of (5) with tris(trimethylsily1)silane (TTMSS)gave markedly different ratios of products (6) depending on the initiator Z E AIBN 17 83 (PhC02)~ 71 29 used. When AIBN is used the E isomer predominates; initiation using benzoyl peroxide leads to the 2 isomer. Further experiments suggest that AIBN is more efficient as an initiator than benzoyl peroxide when utilizing TTMSS as a radical promoter.The tris(trimethylsify1) radicals can undergo reversible addition to the aIkene to furnish the E alkene. Recently Murphy and coworkers have developed a particularly interesting radical process utilizing tetrathiofulvene (TTF)as a promoter.' Thus treatment of diazonium [oo\R1] R2 BF~A2 t-r) C. Ferreri M. Ballestri and C,Chatgilialoglu Tetrahedron Lett. 1393,34,5147. C. Lampard J.A. Murphy and N.Lewis J. Chem. SOC.,Chem. Comun. 1993,295. Reaction Mechanisms -Part (ii) Free-radical Reactions ion (7) with TTFinmoist solvent leads to the adducts (10).The proposed mechanism of these reactions is electron transfer from the electron donor TTF,to the diazonium speciesto generate anaryl radical (8).Thisthen undergoes cyclization and capture with TTFradical-tion to generate (9),which reactswith water to provide product (10).Intermediate (9) has been characterized and shown to react with methanol and acetonitrile to give products (11) and (12). Rhodiumand ruthenium are also beginning to gain an accepted place in the armoury of reagents used to promote free-radical reactions in synthesis. In a full account Ishibashi et at. have reported the synthesis of the naturally occurringalkaloid skeleton (14) using an interesting chiorine atom transfer cyclization. Giese Hartung et al. have been examining rhodium complexes as alkyl radical precursors.’ Although alkylrhodoximes (15) are much less photoreaciive than the ‘H.Ishibashi,N.Ucmurs H.Nakatani M.Okazaki T.&to N.Nakamura and M.Ikcda J.Org. Chem. 1993.58.2360. ’B.Giese J. Hartung C. Kesselheim H.3. Lindner and I. Svoboda Gem.Ber. 1993,126 1193. S. Caddick corresponding cobaloxime reagents they have been shown to participate in a number of reactions. One of the advantages these stable reagents may have over their cobalt counterparts is the ability to act as precursors to tertiary radicals. Hill and co-workers have been investigating the utiIity of polyoxotungstate photocatalysed radical-addition reactions.8 They have found that secondary and tertiary radicals can be generated from the corresponding alkanes oia C-).I activation. These radicals have been utilized in addition reactions with alkenes and alkynes; the reported yields are high at low conversion rates (<10%).Samarium diiodide continues to attract attention as a useful promoter and numerous synthetic applications have been reported. Many transformations promoted by samarium diiodide require additives such as HMPA or DMPU to proceed efficiently. A highly significant study by Nasegawa and Currangdetails investigations of alkyl/aryl halide and carbonyl group reductions with SmI,.They have shown that water is a safeand convenient alternative to the traditional additives and that in halide reductions water accelerates the rate of the reaction. The origin of the enhancement is unclear but it appears that the water does not act solely as a proton source. 3 Intramolecular Reactions General.-In recent years tin and silicon promoted diene and enyne cyclizations have been shown to be synthetically useful procedures.Recently Sirnpkins and coworkers have reportedlo*l analogous cyclizations using the reagents TolS0,SePh or (Ph),PH. The introduction of usefui functionality into the products as illustrated in the isolation of (17) and f19) is idways an attractive feature of this type of transformation. Acyl tellurides have been shown to act as acyl radical precursors;” cyclization of telluride (20) can be promoted by photolysis in very good chemical yields. The retention of the useful vinyl aryl telluride functionality is particularly attractive as the * B.S.Jaynes and C. L. Hill J. Am. Ckem. Sac. 1993 115 i2212. E.Hasegawa and D. P.Curran 3. Org. Chem. 1993. 58 5008.lo J. E.Brumwcll N.S. Simpkins and N. K. Terrett Tetrahedron Lett. 1993,34,1219. J. E. Brurnwcll N. S. Simpkins and N. K. Terrett Tetrahedron Lett. 1993,34 1215. C. Chen and D. Crich Tetrnhedron Lett. 1993,34 1545. Reaction Mechanisms -Part (ii) Free-radical Reactions products can undergo further synthetic elaboration its exemplified in the production of the phenyl selenide product (21) shown. Uneyama and coworkers have also utilized tehride precursors for useful rad-ical-based transformations; in this case however vinyl radicals rather than acyl radicalsare generated. Precursors suchas (22)' have been utilized in an appealingnew indole synthesis; photolysis of (22) leads to good yields of indole (23). Intramolecular radical addition to aromatic systems has also been of recent interest.Ziegler and co-workers have continued their workin the indole area by demonstrating that both di~xolanyl'~ and oxiranyl' radicals derived from thiohydroxamate ester precursors (24) and (26) undergo intramolecular addition to provide entry into enantiomericallypure dihydroindoles (25) and (27).Theinitial photoadduct is a dimer Y.Ueda H.Watanabe J. Wernura and K. Uneyama Tetrahedron Lett. 1993 34,7933. l4 F.E.Ziegler and P.G. Harran J. Org. Chem. 1993 58 2748. Is F. E.Ziegler and P.G. Harran Tetrahedron tett. 1993 34,4505. S. Caddick which can then undergo dissociation and disproportionation to give tbe products shown in moderate yields. ips0 Substitutia-Some recent approaches to the formation of carbon-carbon bonds in aromatic systems employ ipso-substitution processes.Treatment of aryl ether (28) with Bu,SnH/AIBN gives the C-substituted aromatic system (29),16possibly uia an addition-ehnination process. These reactions can proceed efficiently to give rear- ranged products in good yield; however the competing reduction processcandominate if the aromatic ring is not suitably activated with electron withdrawing or donating substituents. An alternative ipsu substitution using sulfonesubstituted aromatic systems has also been reported. Treatment of sulfones (30)with Bu,SnH/AIBN leads to the fused indofe systems (31) in moderate to good yields." (30)n= 1,2,3 (31)n= 1,2,3 In an interesting recent report Cadogan McNab and coworkers" have demon- strated the ability of carboxylic esters to act as radical leaving groups.Flash vacuum pyrolysis (FVP) of aryl ally1 ether (32) leads to the benzofuran derivatives (33) in moderate to good yields (3945%). fpso-substitution is of course not Iimited to aromatic systems; it is now known that acyl germanes can also participate as exemplified in the transformation of (34) to (35). However the related acyl silane (36)undergoes addition and then formally a 'radical Brook' rearrangement to give a cyclopentanol isolated as the benzoate (37). This process has recently been put to excellent synthetic utility; treatment of (38) with alIyl tributylstannane and AIBN followed by desiIylative lactonization gives (40) in reasonable yield." Rearrrrngemeat&-Hydrogen-atom transfer.1,5-€iydrogen abstractions continue to interest synthetic chemists. A notable example is reported by Kraus and Andersh;20 l6 E. Lee,C. Lee,J.S. Tac H. S. Whang and K.S.Li Tetrahedron Lett. 1993,34,2343. l7 S.Caddick K.Aboutayab and R.West SI"LET7+ 1993 231. M. Black J. I.G. Cadogan G.A. Cartwright H. McNab and A. D. MacPhemn J. Gem. Soc. Gem. Commm. 1993,959. l9 D. P. Curran W.-T. Jiaang M. Palovich and Y.-M.Tsai SYNLETT 1993,403. *' G.A. Kraus and B. Andersh J. Chem. Soc. Chem. Commun. 1993,646. Reaction Mechanisms -Part (ii) Free-radical Reactions 0 GePh Ph3Q.H (0.1). AIBN (10%) c 95$ 0 8 ?corn S. Caddick here 1,5-translocation of aryl radical (41) is used to initiate an interesting radical sequence which leads to the formation of (42).MeOvOMe CI CI CJ QWH3 OMe The well-established hydrogen-atom abstraction capability of vinyl radicals is the subject of an illuminating full account by Curran and Shem2' They investigate the effect of substituentson these processesand calculate rate constants (typically lo6s-I). The authors conclude that these hydrogen translocation reactions proceed via an early transition state and parallel 5-exo hexenyl cyclizations with respect to substituent effects. They also suggest that they will find significant use in synthesis. The ability of oxygen radicals to undergo translocation reactions is of course a particularly well known and useful process. In a nice extension of their previously developed chemistry Rawal er al.illustrate a useful isomerization of (43) to OH (431 (44) Although catalytic in principle and practice the authors found that the highest yields were obtained when mediated full equivalent each of Bu,SnH and AI3N was used. 21 D.P.Curran and W. Shen,J. Am. Chem. Soc. 1993,115 6051. 22 V.H.Rawal V.Krishnamurthy and A. Fabre. Tetrahedron ktt. 1993,34,2899. Reaction Mechanisms -Part (ii) Free-radical Reactions Group Transfer. Exciting possibilities exist for radical transformations which involve the transfer of groups as opposed to atoms. Kim and Lim have been investigating the hornolytic 1,5-and 1,6-transfer of the tributyltin group; their recent work has demonstrated that these transfers “45) to (46) and (47); (48) to (49) and (50) (46) (47) (46):(47) 66:34 OH OH (49) (50) (49):(50) 8&:12 respectively] are more favourable than the analogous hydrogen-atom The authors estimate the rate constants for 1,5-and 1,6-Bu3Sn transfer at ca.lo9s-’; the reported rate constant for 1,5-hydrogen transfer is ca. lo8s-’. The 1,2-radical migration reaction generalized below as (51) to (52) has attracted significant interest because of its application to a range of synthetically useful systems. The reaction mechanism is complex and recent studies on B-acyloxytetrahydropyranyl radicals by Beckwith and D~ggan~~ have suggested three mechanistic possibilities concerted via a five-membered transition structure (53a); dissociation into an intermediate radical-cation-anion pair (53b); or 1,2-oxygen shift via a three-membered transition structure (53c).The development of related migration reactions and associated mechanistic investigations are ongoing.26 One particularly nice example is reported by Crich and Yao; treatment of vinyl ether (54) with Bu,SnH leads to the formation of ketone (55) uia a carbon-arbon bond-forming migration process. 27 23 S. Kim and K.M. Lirn Tetrahedron Lett. 1993,34,4851. ’* S.Kim and K.M. Lim J. Chem. Soc. Chem. Commun. 1993,1152. 25 A.L. J. Beckwith and P.J. Duggan J. Chem. Soc. Perkin Trans. 2 1993 1673. 26 D. Cnch and Q. Yao Tetrahedron Lett. 1993 34,5677. *’D. Crich and Q. Yao J. Chem. Soc. Chem. Commun. 1993,1265. 90 S. Cuddick These and other related group-transfer reactions have found synthetic utility in the carbohydrate area.Jung and Tinachoe have recently utilized a stereospecific formyl group transfer for the transformation of (56) to (56a).28 Ring Expansions. Zhang and Dowd continue to demonstrate the generality and synthetic applications of ring expansions which are initiated by addition of car-bon-centred radicals to carbonyl groups.29 In a nice recent development Kim and coworkers have shownJo that aminyl radicals generated from azide precursor (57) will undergo intramolecular addition to a ketone to generate an oxygen radical (57b).This then undergoes j?-scission to give the ring-expanded product (57c) in good to excellent yields. The B-scission ofalkoxy radicals is now a weIl-estabIished path for the initiation of ring-expansion reactions.Recently Pattenden and Schulz have an impres- sive cascade process in which the primary cyclization stepinvolves addition ofa carbon radical to an imine. Thus treatment of cyclobutanone oxime (58) with TTMSSleads to (59) in good yield by the sequence shown below. Met hylene cyclopropanes also serve as useful precursors for ring-expansion reactions oia addition-fragmentation processes asdemonstrated in the transformation of (60) to (61) by Destabel Kilburn and Knight.32 la M.E.Jung and S.W. Tinachoe Tetrahedron Lett. 1993,34,6247. l9 W. Zhang and P. Dowd,Tetruhedron. 1993 49 1965. 'O S.Kim G.H.Joe and J.Y. Do,J. Am. Chem. Soc. 19!33,lt5,3328. G. Pattenden and D.J. Schulz Tetrahedron Lett. 1993 34,6787. 32 C. Destabcl J.D.Kilburn and J. Knight,TetrdedroR Lett. 1993,34 3151. Reaction Mechanisms -Part (ii) Free-radical Reactions (57) Many radicalmediated ring-expansionmethods are based upon the propensity of oxygen radicals to undergo &scission. There are of course a range of methods which can be used €orthe formation of such radicals and these have been used to promote ring-expansion sequences. Rawal and Zhong have dernon~trated.’~that radical- induced ring opening of epoxidescan lead to ring-expanded products; this process can be incorporated into a useful tandem sequenceas shown in the transformations below. 33 V. H.Rawal and H. M.Zhong Tetrahedron Lett.. t993,34 5197. 92 S.Caddick Care is required when choosing the optimum experimental conditions in order to isolate the desired product.0 Im 1-&'3u3SnH (5eq.)AiBN -I0.02MJw.. 15h. 566 benzene C02Et CO2Et Mowbray and Pattenden have used alcohols in impressive sequences;34photolysis of the readily available precursor (68) with iodosylbenzene diacetate and iodine leads to the isolation of (59) in reasonable yield. Further investigations also highlight a potential limitation of the methodology; if a competing hydrogen-atom abstraction is geometrically possible it can lead to significantly reduced yields of desired products. This is however a potential drawback with most methodologies incorporating oxygen-radical intermediates. Booker-Milburn and Thompson have utilized ferric chloride to promote a range of diastereoselective ring-expansion-cyclization reaction^;^' more recently this group 3* C.E.Mowbray and G. Pattenden Tetrahedron Lett. 1993,34 127. 35 K. 1. Booker-Milbum and D. F. Thompson,SYNLETT 1993,592. Reaction Mechanisms -Part (ii) Free-radical Reactions has demonstrated the potential of alternative iron(In) salts. Treatment of (70) with iron(xn) nitrate leads to the isolation of (71) in reasonable yield (49%). Tandem CycUzatioas.-Tstndem cyclizations continue to attract attention from synthetic chemists as methods for formingcomplex polycydic systems. Applications in natural product synthesis are now very common; recent examples include Curran and Shen’s approachj6 to Modhephene utilizing sequential 5-exo-trig cyclizations (72) to (731 and Parson and cowurkers’ tandem approach to lysergic acid derivatives (74) to (75).37 €7’ AC Ac (74) (751 The enediynes have attracted a huge amount of synthetic interest because of their ability to generate diradicals which can be utilized to good effect in biological systems.Grissom et al. have utilized similar materials in ingenious tandem cyclization reactions;38 simple thermolysis of the trienediyne (76)leads to (771 uiu bis-cyclization of the aromatic diradical (75a) itself produced by a Bergman cyclization. A spectacular example of tandem cyclization has been used in a very elegant synthesis of a tetracyclic steroidal skeleton using enyne-allene~.~~ Thermolysis of 36 D. P. Curran and W. Shen Tetrahedron.,1993 49,755. 37 Y.Ozlu D. E. Cladingbocl and P.J.Parsons SYNLETT 1993,357. 38 J. W.Grissom,T. L.Calkins and H. A. McMiIlen J. Urg. Chern. 1933 58 5556. 39 Y. W. Andemichaet Y. Huang and K.K. Wang J. Org. Chem. 1993,s. 1651. S. Caddick precursor (78) leads to the tetracyclic product (79) via the radical cycliz-ation-cycloaddition sequence shown. This useful transformation is particularly noteworthy becauseof the absence of any reagents although the yields are moderate in the cases reported; the authors propose this to be a consequenceof the cycloaddition component of the sequence. The utilization of radical reactions in sequence with efficient cycloaddition reactions is potentially very powerful and likely to find considerable synthetic application in future years. Another unusual and noteworthy tandem cyclization sequence is reported by Harro~ven.~* Treatment of ketenethioacetal (80) with SnBu,H/AIBN leads to thiophene (81); the proposed sequence fox this novel transformation is shown below.4 inte~olecularReactions GeneraLA synthetically useful intermolecular radical reaction is reported by Barton and Zhw4’ White-light irradiation of PTOC esters (82) in the presence of two equivalents of white phosphorus followed by oxidation leads to good yields (70-86%) of aikyl phosphonic acids (83). Competition experiments demonstrated that white phosphorus is a highly efficient trap for alkyf radicals. Some interesting and synthetically useful carbonylation reactions have recently been published demonstrating that the use of ‘slow’ hydride donors such as triphenylger-maniurn hydride leads to improved conversion into carbonylation produ~ts.~’ Thus Gupta and Kahne incorporate a carbonylation into their hydroxymethylation approach using in situ triphenylgermaniurn hydride.Reductive carbonylation of iodide (84) led to (85) in moderate yield. Ryu and coworkers are also active in this area and have recently demonstrated the benefits of TTMSS in mediating free-radical carbonylation. Alkyl and vinyl halides undergo carbonylation using Bu,SnH or TTMSS as promoter; however TTMSS permits the use of lower CO pressures.43 A useful alternative vinylation-allylation sequence has been recently developed by Huval and Singleton;44 in contrast to the use of tin reagents described by Keck and others this work utilizes vinyl and ally1 halides inciuding (86) and (88) to give good yields of addition products (87) and (89).’* D.C. Harrowven Tetrakedron Lett. 1993 34,5653. D.H.R. Barton and J. Zhu J. Am. Ckem. Soc. 1993,lf5,2071. ‘’ V. Gupta and D. Kahne Tetrahedron Lett. 1993 34,591. 43 1. Ryu M. Hasegawa A. Kurihara A. Ogawa S. Tsunoi and N.Sonoda SYNLETT 1993 143. C.C. Huvaf and D.A. Singleton Tetruhedron Lett. 1993 34,3041. Reaction Mechanisms -Part (ii) Free-radical Reactions r- v-L (7w -vw r p H H 195046 Intermolecular addition to aromatic systems continues to be a subject of intensive in~estigation?'~'The Bacchiochi group has demonstrated that a range of systems (Fe"/H,O,; Et,B/O,; Mn'") can promote addition of various alkyl radicals to aromatic systems exemplified in the transformation of (90) to (91).48-51 Other work has demonstrated the ability of organostannyl radicals to undergo " Q-Y-Chen and 2.-T.Li J. Chem. Soc. Perkin Trans. 1 1993 1705. '' M.Yoshida R. Imai Y. Kornatsu Y. Morinaga N. Kamigata and M. Iyoda J. Chem. Soc. Perkin Trans. 1 1993,501. " Q.-Y. Chen and Z.-T. Li J. Chem. Sor. Perkin Trans. I 1993,645. 48 E. Baciocchi and E. Muragha Tetrahedron Lett. 1993 34 5015. '' E. Baciocchi and E. MuragIia Tetrahedron Lett. 1993.34 3799. E. Baciocchi and E. Muraglia J. Org. Chem. 1993,58 7610. E. Baciocchi B. Floris and E. Muraglia J-Org. Chem. 1993 58 2013. S.Caddick 0 (82) (87) (69:31 E:Z) Reaction Mechanisms -Part (ii) Free-radical Reactions (83) (23:77E:Z) (W (911 Reagents i Et,B 0,,benzene or DMSO RI; ii FeSO, H,O, DMSO RI;iii Mn(OAc), NaOAc RH addition to sulfone-substituted aromatic systems as shown in the transformation of (92) to (93).'2 Acyclic Stereocontrol-R-Substituted Radicals.One of the most important recent synthetic developments in free-radical chemistry is the stereocontrolled formation of C-C bonds in acyclic systems. Most investigations in this area have concentrated on substrate-controlkd reactions and further important contributions have been reported in the last year. Giese et al. have recently demonstrated5' that polar groups can enhance the stereoselectivity of 'enolate radical' reductions. In earlier work it had been demonstrated that substituted enolate radicals e.g.from (94),give products which can be explained by invoking a conformation which minimizes A-strain effects. By incorporating polar groups it was found that the degree of stereocontrol was significantly enhanced [from 66 33 (X = Me) to >95 :5 (X= F OMe)] because of the additional unfavourable dipoledipole interactions between X and CO,R in conformer (94b). (Ha) (Mb) '' S. Caddick and S. Khan Tetrahedron Left. 1993 34,7463. 53 B.Giese W. Darnrn F. Wetterich H.-G. Zeitz J. Rancourt and Y. Guindon Tetrahedron Lett. 1993,34 5885. S. Caddick ROZC H (97) (97@ (97u In keeping with this analysis it is found that introduction of a polar substituent at the radicalcentre e.g. from (97),reduces the energy difference between the two conformers.In these cases selectivity decreases when X = Cl OMe and is optimal when X = CH,. Although the use of the A-strain model is useful for predicting stereoselectivity in cases of this type recently Curran and Ramamoorthy have discussed at length54 the fact that such models are not particularly tolerant to substituent effects. In addition to being substrate dependant the stereochemical outcome of many reactions of this type may be additionally dependant on the nature of the incoming reagent. Heteroafom-substituted Radicals. Recent work has suggested that in general a-alkoxy radicals show selectivity which can be explained using the Felkin-Anh rule. Thus Giese and coworkers have optimized the transition states of radicaI (lOO) which undergoes reduction with hydride donor TTMSS.” There are similarities between this type of reduction proposed by Giese to proceed via conformer (lOOa) and the analogous hydride-mediated reduction.Eksterowicz and Houk’s ~alculations’~ support this proposal and go on to show that the radical transition structure is more pyramidahed than the transition state for the corresponding ionic reduction. (100) R = H Si(SiMe& syn :anti 7525 SiiSiMe& Pi (1OOa) s4 D. f.Curran and f.S.Ramamoorthy Tetrahedron,1993.19 4841. ’’ W. Damm J. Dickhaut F. Wcttcrich and B. Giese Tetruhedron Lett. 1993.54.431. s6 J. E. Eksterowicz and K.N.Houk Tetrahedron Lett. 1993 34,427. Reaction Mechanisms -Part (ii) Free-radical Reactions Curran and Sun have examined related systems; early work had demonstrated that nitrogen substituted radicals give syn products which can be explained using the A-strain model.However with a-H-N substituted radicals anti products are obtained; treatment of (101) with TTMSS provides the products (102) and (103).The high degree of anti selectivity can be rationalized by invoking a ‘steric’ Felkin-Anh conformation (101a) or a Cram chelate conformation (lOlb).” I k-SI(SiMe3)3 H-Si(SiMea)j {lola) (101b) Previous studies had demonstrated that simple aIkyl radicals can also participate in highly stereoselective reactions. In a recent investigation Curran Giese and co-workers examined the iodine atom transfer reaction of (104)and (105) which gives in a highly syn-selective manner (106)as the major product (98 :2 syn :anti).These authors propose that the iodine donor approaches conformer (106a) between the medium and large groups and anti to the smallest This transition state minimizes torsional strain as the radical centre pyramidalizes in the transfer process.’’ D. P.Curran and S. Sun TetrahedronLett. 1993,34* 4181. ’* G.Thoma D. P. Curran S. V.Geib 8.Giese W.Damrn and F. Wetterich J. Am Chem. Soc. 1993,115 8585. 100 S. Caddick Reagent-controlled Stereoselectiuity. Some highly diastereoselective reactions have been recently reported by Toru and coworkers.sg In this very exciting development a-sulfinylcyclopentenones (108)were found to undergo jl-addition with t-butyl radicals to give adducts (109) and (110).In the presence of Lewis acid product (109)could be isolated in good yieId; the high degree of diastereoselectivity can be attributed to chelation of the sulfoxide and the carbonyl with the Lewis acid.3x1 the absence of Lewis acid the other diastereoisorner predominated. 0 OV R',LA R k Radicai Sequences.-The use of inter- and intramolecular radical reactions in sequence provides opportunity for the rapid assembIy of complex organic materials. Lee and coworkers have developed an approach to cyclohexenecarboxylates using this type of approach as shown in the transformation of (lll) (112) and (113) to (114).60 Bachi recently disclosed an elegant approach to 8-lactams as illustrated in the transformation of (115) to (l16).61 C02CMe3 C02Me (115) (116) This impressive transformation involves a radical sequence incorporating an inter-molecular radical addition to give (115a) an intramolecular hydrogen atom transfer to provide (115b) and an intramolecular cyclization-fragmentation to give (1 1 Sd).Treatment of (115d) with DBU gives the observed product (116) in reasonable yield. It is interesting to note that this sequence incorporates a relatively unusual '' T.Tom Y.Watanabe M. Tsusaka and Y.Ueno J. Am. Chem. Soc. 1993 115 10444. E. Lee C.U. Hur Y. H.Rhee Y.C. Park and S. Y.Kim J. Chem. Soc. Chem. Commun. 1993,1456. E. Bosch and M.D. Bachi J. Org. Chem. 1993,58 5581. Reaction Mechanisms -Part (ii) Free-radical Reactions (115a) 1115b) 1 1,6-hydrogen atom transfer step.A similar transformation incorporating a 1$transfer was also attempted; treatment of (117) with SnBu,H led to the isolation of (119) as the major product; the desired product (118) was isolated in a disappointing 19% yield. 0qb *q Sn3u3.A'BN 0 Sn0u3 C02Me co*w C02Me (117) (118) 19% (119) 56% A carbonylation component can also be incorporated into synthetically efficient radical sequences as exemplified by the transformation of (I20) to (l2l)in 72% yield.62 5 Applications of Radical Process to Synthetic and Biological Chemistry Synthetic Chemistry.4orey and HeIal have recently developed a convenient enantioselective synthesis of monosubstituted ~xiranes;~~ the utilization of a selective radical dechlorination of chloroalkanes nicely illustrates the potentia1 for radical reactions in sensitive systems.Selective bis-dechlorination of an enantiomerically pure trichloromethyl carbinol (122) gives (123) which under basic work-up gives the oxirane (124) in good yields (>90% ee). The iodine atom transfer method developed by Curran and coworkers is finding significant utility in synthesis; in a full accoud4 Ziegler and Fields describe the application of this powerful methodology to the synthesis of functionaIized penicillins '' I. Ryu H. Yamazaki A. Ogawa N. Kambe and N. Sonoda J. Am. Chem. Soc. 1993 115 1187. 63 E. J. Corey and C.J. Helal Tetrahedron Lett. 1993,34 5227. 64 C.B. Ziegler Jr and T. L. Fieids Tetrahedron. 1993,49 3919. 102 S. Caddick [(125 to (12611.Kawecki and Welch have exploited the iodine atom transfer methodology in the synthesis of functionalized fluoro-8-lactams (128).65 .. n Various alkaloid syntheses have incorporated free-radical t ransformations; Schultz and coworkers have utilized a simple intramolecular Bu,SnH mediated cydization of (129) to give (130) in their synthesis of (+)-l-deoxylycorine.66 The application ofBn,SnH in alkaloid synthesis is niceIy expIoited by Bonjoch Sulk and Bosch; in an impressive one-pot transformation (13 1) undergoes desulfurization and reductive cyclization to give tubifolidine (132) in 50% Biotogicrrl Ckntistry.-The enediynes continue to attract a great deal of attention; C-1027 chromophore is a particularly interesting addition to this fascinating family of natural products.Yoshida and coworkers have recently shown that this molecule (133) which exhibits DNA cleaving capabilities can undergo a direct rapid cyc-" R. Kawecki and J.T. Welch Tetruhedron Lett. I993,34 3087. 66 A.G. Schult M.A. Holoboski and M.S. Smyth J. Am. Chem. SQC. 1993 115,7904. 6' J. Bonjoch D. Sole and J. Bosch. J. Am. Chem. Sm. 1993 115 2064. Reaction Mechanisms -Part (ii) Free-radical Reactions ioaromatization to give the potentially DNA-damaging benzenoid diradical (134).68 The enediynes have stimuIated an increased interest in the interaction of car-bon-centred radicals with DNA because of the prospect of developing therapeutic agents. Breem and Murphy have shown69 that certain simply vinyl epoxides react with thiol radicals to generate DNA-damaging oxygen-centred radicals; they "K.Yoshida Y.Minami R.Azuma M. Sacki and T.Otani Tetrahedron Lett. 1993,34 2637. 69 A. P.Breen and J.A. Murphy J. Chem. Soc. Chem. Convnun. 1993 191. 104 S. Caddick then report7* the DNA-cleaving capabilities of substrate (135) which is readily synthesized and incorporates a phenanthrohium unit fa known DNA intercalator). Treatment of commercially available supercoiled DNA with (1351 glutathione and horseradish peroxidase leads to DNA strand cleavage; control experiments show that the deavage is dependant upon the presence of the glutathionyl radicals. '* A.P. Breen and J. A. Murphy J. Chem. SOC. Perkin Trans. I 1993 2979.

ISSN:0069-3030    

DOI:10.1039/OC9939000081

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

5 Aliphatic and Alicyclic Chemistry By P. QUAYLE Department of Chemistry The Victoria University of Manchester Manchester M 13 9PL UK 1 Introduction This has been a good year for synthetic organic chemistry as shown by no less than three’ total syntheses of the immunosuppressive agent rapamycin (I).These embody a range of synthetic methodology which was only recently deemed esoteric including Stille cross-coupling reactions samarium-promoted Tischenko reactions and tita- nium-mediated aldol reactions. Application of the traditional skills of the synthetic organic chemist to increasingly more complex biological problems’ is well dernon- strated in Schreiber’s studies of the synthesis of FK-506 derived ligands capable of binding pr~teins.~ In a similar vein the use of biochemical techniques to solve chemical problems is ever more apparent as witnessed by the number of reviews in this area particularly noteworthy are appraisals of the use of catalytic antibodies4 in organic synthesis.On more familiar ground extensive reports on the use of enzymes in organic synthesis’ and a review on chemoenzymatic approaches6 to azasugars provide much useful information and stimulus. Other major research themes in recent years -supramolecular chemistry’ and molecular recognition* phenomena -have again enjoyed extensive coverage. In new synthetic methodology organometallic chemistry continues to provide K.C. Nicolaou T.J. Chakraborty A.D. Piscopio,N. Minowa and P. Berttnato,J. Am. Chem. SOC. 1993 115,4419;D.Romo,S.D.Meyer D.D. Johnson and S. L. Schreiber 1.Am. Ckem. Soc. 1993,115,7906; C. M.Hayward D. Yohannes and S.J. Danishefsky J. Am. Chem. Soc. 1993 115 9345. A.T. Sneden SYNLETT 1993 313; R.S. Varma SYNLETT 1993,621; G.G. Cross and T.M. Fyles SYNLETT 1993,449;R.S. Varma SYNLETT 1993,621;M Kahn SYNLETT 1993,821;A. Giannis and T. Kolter Angew. Chem. Int. Ed. Engl. 1993,32,1244;C.Unverzagt Angew. Chem.,Int. Ed. Engl. 1993,32 1691;C.A.A. van Boeckel and M. Petitou Angew. Chem. Int. Ed. Engl. 1993,32 1671. D.M.Spencer,T. J. Wandless S. L. Schreiber and G. R.Crabtree Science 1993,262,1019; M.B.Andrus and S. L. Schreiber J. Am. Chem. Soc. 1993 115 10420. ‘C. Laumann Angew. Chem. Int. Ed. Engl. i993,32,1291;P.G.Schultz and R.A. Lerner Ace. Chem. Res. 1993,26,391;D.Hilvert Acc.Chem. Res. 1993,26,552. D.H.G. Crout S. M. Roberts and J. B. Jones Tetrahedron Asymmetry 1993,4 757; 1081. G.C.Look,C.H. Fotsch and C.-H. Wong Acc. Chem. Res. 1993 26 182. ’S. Shinkai Tetrahedron 1993,49 8933; S. Anderson H. L. Anderson and J.K. M.Saunders Acc. Chem. Res. 1993,26,469;Top.Curr.Chem. 1993,165;R. M.Izatt and J. S. Bradshaw Pure Appl. Chem. 1993,65 355;D. N.Reinhoudt Pure Appl. Chem. 1993,65,2313;A.F.Danil De Namor Pure Appl. Chem. 1993,65 1457. * T.H.Webb and C.S. Wilcox Chem. SOC.Rev. 1993,22,383;K.E.Krakowiak J. S. Bradshaw and R.M. Izatt SYNLETT 1993,611;2.Asfari J. Weiss and J. Vicens SYNLETT 1993,719;N.T. Thuong and C. HeIene Angew. Chem. lnt. Ed. Engl. 1993 32 666. f 05 106 P. Quayle I H Me fruitful avenues for investigation,' especially in the development of new asymmetric reactions." Asymmetric methodology in general' 'continues to be a recurrent theme as is the use of free-radical reactions in organic synthesis.' Environmental consider- ations have prompted investigation of reactions carried out in the solid state13 and in aqueous s~lution'~ rather than in organic solvents.There has been renewed interest also in the application of photochemical' and electrochemica1l6 techniques to organic synthesis. The search for complex medicinal agents17 and the isolation of novel structural types,18 most notably from marine sources,19 continues to pose enormous rnethod- ological challenges,20 and few molecules are more challengingthan the enediyne family P.Knochel and R.D. Singer,Chern.Rev.,1593,93,2117;Y. Yamarnoto and N. Asao Ckem. Rev. 1993,93 2207; B. knnetau and J. Dunogues,SYNLETT 1993,171;S.G. Davies and T. J. Donohoe SYNLEJT 1993,323;U.Schuchardt W.A.Carvalho and E. V. Spinace SYNLETT 1993,713;P.Wipf Synthesis 1993,537;K.Ritter Synthesis 1993,735;G. G.Melikyan Synthesis 1993,833;A. Furstner Angew. Chem. Int. Ed. Engi. 1993,32,164;J. Sundermeyer Angew. Chem. Int. Ed. Engt 1993,32,1I44;Y.Nishigaichi A. Takuwa A. Tauwa Y.Naruta and K. Murayama Tetrahedron I993,49,7395;M.Schlosser,0.Desponds, R.Lehrnann E. Moret and G. RauchschwaIbe Tetrahedron 1993,49,10 175; A. J. Pearson Tetrahedron 1993,49 5415; 3.H-Rigby Acc. Chem. Res. 1993,26 579. lo J.M. Brown Chem. SOC. Rev. 1993 22,25; C.Bolm Angew. Chem.Int. Ed. Engl. 1993,32 232;W. Hernnann and C.W.Kohlpaintner Angew. Chem. Int. Ed. Engl. 1993,32,547;0.Reiser Angew. Chem. Int. Ed. Engl. 1993,32,547; A. pfaltz Acc. Chem. Rex 1993 26 39. A. H.Hoveyda D. A. Evans and G. C. Fu,Chem. Rev. 1993,93,1307;K.Fuji Chem. Rev. 1993,93,2037; M. Lautens SYNLETT 1993 177; S.W.McCombie 1993,807;L. Banfi Synthesis 1993,1029;H. Kunz and K. Riick Angew. Chem. Int. Ed. Engl. 1993,32,336;B. H. Kim and D. P.Curran Tetrahedron 1993 49,293;D.J. Ager and M.B. East Tetrahedron i993,4!?, 5683;K.Koja and T. Shioiri Tetrahedron 1993 49,1711; M.T.Reetz Acc. Chem. Res. 1993,26,462;K.Sakai and H. Suemune Tetrahedron Asymmetry 1!?93,4,2109. I' A.L. J. Beckwith Chem. Soc. Rev. 1993,22 143; P.Dowd and W.Zhang Chem. Rev. 1993,93,2091.l3 F.Toda SYNLETT 1993 303. l4 C.J. Li Chem. Rev. 1993,93 2023. l5 M. T. Crimrninsand T.L. Reinhold Org. Reuct. 1993,44,297;G.Pandey Top. Cum. Chem. 1993,168,175. l6 M.E.Niyazymbetov and D. H. Evans Tetrahedron 1993 49 9627. l7 P.W.Collins and S. W. Djuric Chem. Rev. 1993,93,1533;H.Kessler Angew. Chem. Int. Ed. Engf.,1993 32,543;S.F.Wunk Tetrahedron 1993,49,9877;S. L. Beacage and R.P. Iyer Tetrahedron 1993,49,10441. '* J. P.Michael and G. Pattenden Angew. Chem. Int. Ed. Engl. 1993,32 1. l9 D.J. Faulkner Cltem. Rev. I993,93 1671; D. J. Faulkner Top. Curr. Chem. 1993,167. 'O R. Gleiter and D. Kratz Angew Chem. Int. Ed. Engl. 1993,32,842. Aliphatic and AIicyclic Chemistry 107 of antitumour agents.” Recent advances in the development of more concise approaches to complex molecules are reviewed in two timely articles on double-Michael reactions22 and ‘sequential reactions’.23 Ultimately fundamental advances in synthetic design will depend upon a more quantitativez4 appreciation of stereochemi- cal and electronic factors controlling organic reactivity.These considerations are doubtless responsible in part for the continuing intense interest in the chemistry of C, and related compounds.2s The possibility of synthesizing molecular arrays possessing some characteristics of living organisms has been addressed.26 Advances in this area may have fundamental impIications but it is a sobering thought however that our understanding of complex biosynthetic problems (e.g. B 2) is still in~mplete.~’ 2 Alip&aticChemistry General.-The synthesis of planar four-coordinate carbon compounds has been reviewed.z8 OlahZ9 has presented a fascinating overview on his work on ‘super electrophiles’.Rearrangement reactions are frequently used in organic synthesis and several timely accounts of current progress in this area have appeared.30 The synthetic amine #l-la~tones,~* appIications of a-amino acids:’ alko~yallenes,~~ and organ~fluorine~~ compounds provide much interesting reading. Organic synthesis still relies heavily upon protecting group strategies for functional group differentiation and two excellent reviews dealing with use of silicon-based protecting groups for alcohobJ6 and with esters as a protecting group for carboxyl f~nctionality,~~ have appeared.Heteroatom-based rnethod~logies,~~ in particular those of phosphorus and selenium have transformed contemporary organic synthesis. Reich’s review39 on selenoxide eliminations in particular provides many useful pointers for the practising synthetic chemist. An extensive review of the Baeyer-ViIliger oxidation of aldehydes and ketones is also most welcome.** There have been theoretical studies on a number of text-book reactions including ” M.M. Campbell M. Sainsbury,and P.A. Wle Synthesis 1993,179; R. E. Wolf Pure Appf.Chem. 1993 65 1103; J.-C. Harmange and Figatere Tetrahedron Asymmetry 1993.4 1711. ” M. Ihara and K. Fukumoto Angew. Chem. Int. Ed. Engl. 1993,32 1010. ” L.F. Tictzc and U. Btifuss Angew. Chem. Int. Ed. Engl. 1993 32 131.’’ J.E. Eksterowicz and K.N.Houk,Chem. Rev. 1993 93 2439; 1. Ugi J. Bley A. Dengler A. Dietz E. Fontain B.Gruber R.Herges,M. Knauer,K.Reitsam and N. Stein Angew. Chem.,Int.Ed. Engf.,1993,32 201; C.D. Johnson Acc. Chem. Res. 1993 26,476. ’’ A. Hirsch Angew. Chem. Int. Ed. Engt. 1993,32,1138; H.Schwartz Angew. Chem. lnt. Ed. En& 1993.32 1412. 16 D. W.Urry Angew. Chenr. Int. Ed. Engl. 1993,32 819. ’’ A.1 Scott Angew. Chem. Int. Ed. Engl. f993,32 1223. M. Albrecht G. Erker and C.Kriiger SYNLETT 1993.26. 29 G.A. Olah Angew. Chem. int. Ed. En& 1993.32 767. S.R. Wilson Org. Reuct. 1993,43,93; R. F.C.Brown and F. W. Eastwood SYNLETT 1993 9; H. R. Sonawanc N. S. Bellur D. G. Kulkarni and J. R. Ahuja. SYNLETT 1993,875; J.-L. Ripoll and Y.Vallee Synthesis 1993,659; H.M.L.Davits Tetrohedron 1993,49 5203. ” A. Golebiowski and J. Jurczak SYNLETT 1993 241. ” R. Zimmer Synthesis 1993 165. 33 A. AIbini Synthesis 1393 263. ” A. Pommier and J.-M. Pons,Synthesis 1993,441. ” H. Uno and H. Suzuki SYNLETT 1993 91; G. Resnati Tetrahedron 1993 49 9385. 36 J. Muutrt,Synrhesis,1993.11; C.J. Salonton,E.G.Mata and 0.A. Mascaretti Tetrahedron 1993,49,3691. 31 A. Fava Pure Appf.Chem. 1993,65 595. 38 r. ugi Synthesis 1993 I. 39 H. J. Reich and S. Wollowitz Org. Rear. 1993,44,4. ” G.R. Krow Org. Reuct. 1993,43 251. 108 P.Quayle Michael additions:’ the SN2-E2 spectrum,42 pinacol rearrangement^:^ and elec- trophilic additions to alkene~.~~ Many stereocontrolled reactions involve the interac- tion of a carbonyl group with one or more metal centres.Much experimental evidence concerning the mode of such interactions has appeared this ~ear?~-~O The use of strong bases (e.g. Bu”Li/TMEDA) is now common place but often with little understanding of the nature of the species reacting in the medium. Recent mechanistic studiessi and an authoritative survey of organoalkali metal structuress2 should promote such understanding and perhaps encourage more efficient use. An evalu-ation of directing groups in ortho-lithiation reactions poses a number of interesting mechanistic questions. 53 A theoretical investigation into the generalized anomeric effects4 and further reports onthe transition state structures involved in cyclohexanone reductions have appeared.The ability to prepare probes containing chiral methyl groups has had a profound effect upon our understanding of a number of biosynthetic pathways. A personal account of work in this area is most instr~ctive.~~ Coupling Reactions.-Synthetic methods concerned with carbon-rbon bond forma-tion continue to be a major preoccupation. Variants on the Heck and StiHe cross-coupling reactions for the stereoselective formation of olefins are abundant (Schemes 1-1 l).57-68 A growing body of empirica1 evidence suggests that the addition of copper(i) salts as a cocatalyst in such reactions may have a pronounced effect upon the rate-determining transmetallation step.69 In several cases reaction times are L. Pardo R. Osman H. Weinstein and J. Rabinowitz J. Am. Chem.SOC. 1993,115 8263. ” S. Gronert J. Am. Chem. Soc. 1993 115 652. 43 K. Nakamura and Y.Osamura J. Am. Chem. Soc. 1993,115,9112. “ M. Fujita M. Ishida K.Manako K. Sato and K.Ogura Tetrahedron Lett. 1993,34,645. ‘’ S.E.Denmark and N.G. Almstead J. Am. Chem. Suc. 1993 115,3133. “ S. Castellino and W. J. Dwight J. Am. Chem. Soc. 1993 115,2986; P. G. Willard and Q.-Y. Liu J. Am. Ckem. Soc. 1993,115 3380. 47 H. Sasai T.Suzuki N. Itoh K.Tanaka T. Date K. Okamura and M. Shibasaki J.Am. Ckem. Soc. 1993 115 10372. ’* G. Quinktrt H. Becker M. Del Grosso G. Dambacher J. W. Bats and G. Durner Tetrahedron Letr. 1993 34 6885. 49 M.P.Bernstein and D. B. Collum J. Am. Chern. Soc. 1993 115 789. ” M.Sirnard J. Vaugeois and J.D. Wuest J. Am. Chem. Soc. 1993 115,370. ” F.E.Rosenberg M. P. Beernstein,J. Gilchrist A. T. Harrison D. J. Fuller and D. B. Collum,J. Am. Chem. Suc. 1993 115,3475; M. A Nichols and P.G. Willard J. Am. Chem. Soc. 1993,115 1568. ” E.Weiss Angew. Chem. Int. Ed. Engl. 1993 32 1501. ” P. Beak S-T. Kerrick and I).J. Gallagher J. Am. Chem. Soc. 1993 115 10628. s4 U. Salzner and P. Yon R. Schleyer J. Am. Chem. Soc. 1993 115 10231. ” 1. M.Coxon and R.T. Luibrand Tetrahedron Lett. 1993,34,7097; Y.Wu and K.N. Nouk J. Am. Ckem. Suc. 1993 115 10992. ’6 H.G. Floss and S. Lee Acc. Chem. Res. 1993 26 166. ” P. MeInyk J. Gasche and C. Thal Tetrahedron Lett. 1993 34 5449. A.R. Hunt S.K.Stewart and A. Whiting Tetrahedron Lett. 1993 34 3599. ” T. Sakamoto Y.Kondo N. Takazawa and H. Yamanaka Tetrahedron Lett.t993,34 5955. 6o D.A. Evans and T. Bach Angew. Chem. Int. Ed. Engl. 1993,32 1326. 61 H.Finch N.A. Ptgg and B.Evans Tetrahedron Lett. 1993,34 8353. ” J. P.Michael S.-F. Chang and C. Wilson Tetrahedron Lett. 1993,34,8365. D. Badone and U. Guzzi Tetrahedron Lett. 1993 34 3603. 2. Xu and J. S. Moore Angew. Chern. Int. Ed. Engl. 1993 32 1354. S. W. Lee and P. L. Fuchs Tetrahedron Lett. 1993,34,5209; Z.Jin and P. L. Fuchs Tetrahedron Lett. 1993 34 5205. ‘‘T. JeKery Tetrahedron Letr. 1993 34 1133. 67 M.Amat S. Hadida and J. Bosch Tetrahedron Lett. 1993,34,5005. K.F.McClure and S.J.Danishefsky J. Am. Chem. Suc. 1993 115 6094. 69 R.3. Hinkle G. T. Poutter and P.J. Stang J. Am. Chem. Soc. 1993 115 11 626; see also J. M.Saa and G. Martnrell .I Om Ch~m1993 9.1963 for related observations.Aliphatic and Alicyclic Chemistry 109 (ref 57) Reagents i Pd(OAc), Ph,P Bu,NBr K,CO, DMF Scheme 1 Reagents i Pd(OAc), NEt, CH3CN 80"C Scheme 2 (ref 59) Reagents i Zn*;ii ArX Pd(PPh3), THF 80"C scheme 3 Scbeme 5 110 P.Quayie (ref 62) Reagents i proton sponge Pd(OAc), DMF,80°C scheme 7 (ref 65) Reagents i P~(OAC)~, AgOAc DMF,45 "C Aliphatic and Alicyclic Chemistry Reagents i Pd(o) NEt, CH,CN 80°C scbeme 11 reduced and yields are higher especially in those reactions which are sluggish when using Pd(0) alone Scheme 12. Remarkably Piers has shown that in at least one system the palladium cataIyst can be dispensed with altogether if stoichiometric quantities of copper chloride are added Scheme 13.’* This result obviously warrants further investigation.(ref 69) Reagents i PdCIBn(PPh,), CuCI DMF,rt scheme 12 Reagents i CuCI (2.2 q),DMF 62 “C,3 min Scheme 13 ‘Contrasteric’ functionalization of 1,l-dihaloalkenes has been observed in Heck or Stille reactions by a number of workers.” The generation of chelated vinyl palladium species has been invoked in order to rationalize these observations (Scheme 14). The use of vinyl boronic acids72 (Suzuki crosscoupling) and vinyl ~iIanes’~ in Stille-type reactions continues to gain acceptance (Scheme 15). Cascade sequences which uti€ize 70 E. Piers and T. Wong J. Org. Cfiem. 1993 SB 3609. 7’ J. Suffert A. Eggcrs S. W. Scheupkin and R. Bnrckner Tetrahedron Lett.1993,34,4177; S. Toni H. Okumoto T. Tadokoro A. Nishimura and M.A. Rashid Tetrahedron Lett. 1993,34,2139; J. M. Nuss R. A. Rennels and 6.H. Lcvine J. Am. Chem.Soc. 1993,11S 6991; for related examples in organolithium chemistry see D. Grsndjcan and P. Pak TetrahedronLett. 1993,34,1155; M.Braun and K.Opdenbusch Angew. Cktn. Int. Ed. Engl. 1993,32 578. 72 N.Yrtsuda L. Xavitr D.L.Riegtr Y. Li A.E. DcCamp and U.-H. Dolling TetrahedronLett. 1993.34 3211. 73 K. Takahashi T. Minami Y. Ohara and T. Hiyama Tetrahedron Lett. 1993,34 8263. 112 P. Quuyb scheme 14 Reagents i Pd(dbq), THF KOHtaq) rt; ii TBAF P(OEt), Pd(o) Scheme IS sequential Heck and carbonylation reactions have been reported by Grigg (Scheme 15).74 The use of ketone enolates in palladium-mediated cross-coupling reactions has hitherto been neglected but a line example demonstrating the synthetic potential of this reaction is featured in Albizati's synthesis of (+ )-hapallindole Q (Scheme 17).7' (ref 74) Iso2m Isoph Rcsgents:i Pd(o) CO CH3CN TlOAc Scheme 16 The stereospecific cross coupling of a homochiral a-aIkoxystannane with an acyl halide has been reported by Fal~k'~ in his synthesis of(+ kgonifuranone (Scheme 18).The stereochemical course in this reaction wasopposite to that expected; further work in this area is required in order to ascertain the generality of this observation. Modifications77*78 of well-established copper-mediated carbon-carbonbond-form-'' R. Grigg and V. Sridharan Tetrahedron Left.1993 34,7471. " V. VaiIlancourt and K. F. Albizati J Am. Chem. Sac, 1993,115 3499. 76 J. Ye R.K. Bhatt and J. R. Falck Tetrahedron Lett.. 1993. 34,8007. " M. BergdahI M. Eriksson M. Nilssan and T. Olsson J. Org. Chem. 1993,58 7238. '' J. Westermann and K.Nickisch Angew. Chem. Int. Ed. Engl. 1993.32 1348. Aliphatic and Alicyclic Chemistry i (ref 75) Br& 50% + Brl--OAc I TIPS I TlPs Reagents i Bu,SnOMe Pd(o) toluene 100"C Scheme 17 (ref 76) Reagents:i PhCOCI PdCI,(PPh3), CuCN toluene 80°C Scheme 18 ing reactions continue to be the focus of attention (Scheme 19).A major advance this year includes the use of organolithium zincates as a 'soft' source of organoIithium reagents in the conjugate addition reactions of enones.Kn~chel~~ has published full experimental details of the preparation of the synthetically versatiIe functionalized organometalIics (2) (Scheme 20). Reagents i LiI TMSCI Scheme 19 (ref 79) (21 Reagents i Zn,THF 12°C; ii CuCN-2LiCI,3O0C,DMF;iii E+ Scheme 20 Asymmetric Catalytic CoupIing Reactions-Asymmetric Heck reactions as developed by Shibasaki have been utilized in the synthesis of indolizidine a~kaloidssOand in a '9 P. Knochel T.S. Chou C. Jubert and D. Rajapohal J. Org. Chem. t!393,58 508; M. J. Rozema C. Eiscnberg H. Lutjens R. Ostwald K. Belyk and P. Knochel Tetrahedron Lett. 1993 34,31 15. S.Nukui M.Sodcoka and M. Shibisaki Tetruhedron Lett. 1993 34,4965. 114 P. Quayle total synthesis of (-))-eptazocene (Scheme 21).81 Ligand systems which enable enantioselective palladium-catalysed allylic substitution reactions have again been the subject of numerous reports." Several authors have demonstrated that oxazo-line-derived ligands can induce high levels of enantioselectivity in these reactions (Scheme Z).82*83 Pfaltzg4has also demonstrated that ligands such as (3) enable the enantioselective 1,4-addition of Grignard reagents to enonesin poorto moderate levels of induction (1683% e.e.) (Scheme 23).(ref 81) Reagents i Pd*Lm, Ag'; ii Pd*(o) (ref 83) Reagents i 1 mol % [(Pd(C,H,)CI},J 2.5 mol % L*. BSA,KOAc. CH,Cl, 23 "C;ii [(Pd(C3H5)CI},]L* scheme 22 '* S.Takernoto M.Sodeoka H.Sasai and M.Shibasaki,J. Am.Chem. Soc. 1993,115,8477. 81 P.von Matt and A.Pfaltz Angew. Chem. lnt. Ed. Engf. 1993 32,556. '' G.J. Dawsoon C. G.Frost,C.J. Martin,J. M.J. WiIliarns and S. J. Coote TetrahedronLett. 1993.34,7793. Q.-L. Zhou and A. Pfaltz TetrahedronLett. 1993 34,7725. Aliphatic and Alicyclic Chemistry 0 0 Akenes and Polyeaes-Schlosser has developed a general method for the synthesis of Z vinyl halides8' using the modified Wittig reagents (4).Erythro phosphinyl alcohols (5) afford E olefins upon exposure to PCI and NEt, in a reaction similar to a Ramberg-Backlung rearrangement (Scheme 24).86 (ref 85) Reagents i,THF 50 "C; ii XI,,NE!,. CH,Cl, 0°C !scheme24 DenmarkB7 has reported a highly stereoselective synthesis of trisubstituted olefins,a structural motif present in many natural products but difficult to introduce in a stereoselective fashion using existing Wittig methodology (Scheme 25).Two OH BU' Reagents i THF 105 "C X.-p. Zhang and M.Schlosser,Tetrahedron Lett. 1393 34,1925. N. Lawrence and F. Muhammad 3. Chem. Soc. Chem. Comnnm. 1993 1187. S. Dcnmark and .I.Amburgey J. Am. Cfrem. Sm. 1993 115 10386. 116 P.Quayle i. ii 1 (>80% dc) (ref 88) (ref 89) Me02C H OTBDPS Reagents i KHMDS 18-C-6 -100°C; ii NaBH,; iii NaH -78 "C;THF Scheme 26 gro~ps~~~~~ have described the use of homochiral Wadsworth-Emmons reagents for the desyrnmetrization of meso carbonyl compunds (Scheme 26). Similarly,the kinetic resolution of xacemic ketones" using the phosphonate (6) afforded trisubstituted alkenes with usefuI Ievels of asymmetric induction (Scheme27).The use of homochird 0 ,-*z F% (ref 90) 38% (89%e.e.) (6) Reagents i KHMDS THF -80°C &kme 27 '' N. Kann and T. Rein J. Org. Chem. 1993 58 3802. 89 K. Tanaka Y. Ohta K. Fuji and T.Taga TetrahedronLett. 1993 34,407. 90 K. Narasaka E. Hidai Y. Hayashi and J.4. Gras J. Chem. Soc. Chem. Commun. 1993 102. Aliphatic and Alicyclic Chemistry bases in asymmetric elimination reactionsgi also appears to be an attractive route to scalemic exocyclic olefins (Scheme 28). Bu' 1 (ref 91) H02C' Qrganozirconiurn reagents have been used in several guises for the stereoselective synthesis of alkenes and polyenes (Scheme 29).92-94 In a ground-breaking develop- (ref 94) R-gents i 2 x EtMgBr; ii RC=CR; iii R,CHO; iv H,O+; v 35°C;vi H,O+ rt; vii cat.AgClO, Ff 30min; viii. H,Ot Scheme 29 ment two groupshave reported the use of anolefin metathesis strategy fur the synthesis of functionalized olefins (Scheme 3U).95+96Applications of this methodology will doubtlessarise in the nearfuture.The related Tebbe-mediated synthesis ofolefinsfrom unactivated carbonyl compounds (esters etc.) has been extensively re~iewed.~' 3. Vadecord J.-C. Plaquevent L. Duhamel and P. Duhamel J. Chem. Soc. Chem. CO~~UR., 1993 116. " T. Takahashi M. Kageyama V. Dcnisov R. Ham and E. Negishi Tetrahedron hrt. 1993,34 687. 93 T. Takahashi N. Suzuki,M. Kageyama D. Y. Kondakov and R.Hara TetrahedronLett. 1993,34,481I. '' H. Maeta and K. Suzuki Tetrahedron Lett.I993,34 341. 95 G. C. Fu and R. H. Grubbs,J. Am.Ckem.Soc. 1993,115,380O; G.C Fu S.T.Nguycn,and R.H.Grubbs,J. An.Chem. Soc. 1993 115,9856. 96 H. Junga and S. Blcchcrt Tetrahedron Lett. 1993,34,3731. " S.H. Pine Org. React. 1993 43 1. 118 P.Quayle (ref 95) Reagents i Mo catalyst benzene 20 "C;ii MTO/SiO, Ai,O, CH,€l, rt scbeme 30 Transfer hydrogenation ofacetylenesg8 has been shown to occur under mild reaction conditions to provide 2 olefins with levels of high stereochemical purity (typically Z E > 97 :3). y-Hydroxy-a,fLynones are cleanly transformed into E,E dienones upon treatment with triphenyf phosphine." SaladieloOhas reported a highly stereoselective synthesis of trienes uiu a 1,6 reductive4rnination sequence (Scheme 31).Reagents i TiCI, LiAlH, THF 65 "C scbeme 31 The Ramberg-Backlund reaction has been applied with good effect in the synthesis of unsaturated a-amino acids without loss of stereochemical fidelity (Scheme32)."' 1-Nitroalkenes are transformed into *unsaturated nitriles in a one-pot sequence (Scheme 33).Io2 98 K. Tani N.Ono,S. Qkamoto and F. %to J. Chem. Soc. Chem. Commun. 1993 386. '' G. Guo and X.Lu,J. Chem. Soc. Chem. Comn. 1993,394. loo G. Solladie G. B. Stone and A. Rubio Tetrahedron Lett. 1993 34,1803. 2.-X. Guo,M.J.Schaeffer and R.J. K. Taylor J. Chem. Soc. Chem. Commun. 1993,874. H.-W. Tso RA. Gilbert and J. R.Hwu J. Chem. Soc. Cfrem. Conrmun. 1993,669. Aliphatic and Alicyclic Chemistry DN0* -fil (ref 102) 10% Reagents i Me,SiCH,MgCl; ii XI, THF scheme 33 Stereoselective functionaiization of olefins continues to be an area of much methodological interest.*03 Of note this year is the report of a paIladium-catalysed asymmetric acetalization ofacryIamides (Scheme 34),"* the stereoselective cyclization t Ph-0 OMe (ref 1w 0U OI M e Reagents i MeOH PdCl, CuCi, O, rt; ii PhCH,OLi scbeme34 of 3-aminopent-1-en-5-01sto the corresponding tetrahydrofurans (Scheme 35),'05 and an asymmetric synthesis of a-amino acids via a stereoselective iodolactonization reaction (Scheme36).lo6 Details ofan asymmetric selenoetherification reaction have also appeared (Scheme 37).'*' Epxides Dids ad Related Compwds.-The Sharpless enantioselective dihyd- roxylation (ADHT)of achiral olefins has been the focus of mechanistic investigation; two distinct interpretations of kinetic data have been advanced.lo' Sharpless favours a non-concerted [Z + 23 cycloaddition-rearrangement reaction rather than a classical lo' J.Rodriguez and J.-P. Dulcert Synrhesis 1993 1177. lo4 T.Hosokawa and S.-i. Murahashi J. Chem. Soc. Chem. Convnun. 1993 117. lo' Y. Tarnura,H. Harayama and T. Bando J. Chem.Soc. Chpm. Cammun. 1993 1601. lo' 0.Kitigawa T.Hamno N. Kikuchi and T. Taguchi Tetrahedron Lett. 1993.34 2165. R. Dtzitl R.Goulet L. Grenier J. Bodeltau and J. Bernicr J. Org Chpm. 1!?93,S8 3619. IonE.J. Corty M.C.Noe and S.Sarshar,J. Am.Ch.Soc. 1993,115,3828; H.C. Kolb P.G. Andcrsson Y.L. Bcnnani G.A. Crispino K.4. Jeong H.-L.Kwong and K. B.Sharpless J.Am. Chem. Sm.,1993 115 12 226. 120 P. Quayle Reagents i I, NaHCO, O'C H,O Et,O Scheme 35 Scheme 36 9PMB i ii Oet SmfqB 51%(ca90%e.e) (ref 107) Reagents i pMBA; ii Ph,SnH AIBN Scheme 37 [3 + 21 cycloaddition process. Irrespective of mechanistic detail this experimentally simple reaction is now an indispensiblesynthetic tool as shown below (Scheme 38).'09 (+)-exo-brevicomin Reagents i OsO, (DHDQ),-PHAL; ii TsOH Scheme 38 J. A. Sodcrquist and A. M. Rane Tetrahedron Lett.. 1993 34,5034. Aliphatic and Alicyclic Chemistry Other workers have aIso developed both catalytic (Scheme 39)' and stoichiomet- 'On' ric (Scheme @)'I2 variations which in several instances are cornpIementary to the Sharpless system.L* = cG(R OH Y = neohexyl) R f Reagents i OsO, L* CHJl, -8 'C;ii Na,S,U Scheme 39 Reagents i OsO, L* toluene -90°C Scheme 40 Diastereoselective'' and enantioselective' I4 epoxidation reactions continue to be exploited synthetically (Scheme 41). Jacobsen's enantioselective epoxidation provides particularly rapid access to a range of functionalized olefins which are useful in Reagents i Bu'OOH 0.5 eq Ti(OPr'), L-( + )-DIPT -16 "C Scheme 41 'Io E.J. Corey M.C. Noe and W.-C. Shieh Tetrahedron tert. 1993 34 5995. 'I1 T. Oishi K. lida and M. Hirama Tetrahedron Lett. 1993,34,3573. 'I2 S. Hanessian P. Moffre M.Girard S. Beaudon J.-Y.Sanceau and Y. Bennani J. Org. Chem. 1993,518 1991. 'I3 J. Clayden E. W. Collington R. 3. Lamont and S.Warren Tetrnhedrun Lett. 1993 34 2203. 'I4 E.J. Allain L. P. Hager L. Deng and E. N. Jacobsen J. Am. Chem. Soc.. 1993 115 4415. f 22 P.Quayle 1 62%(!32%e.c.) 1 RO (CH2)3C02Me (ref 115) HQ-H Reagents i Mn cat NaOCI pH 11.5 !3cbeme 42 target-orientated synthesis as demonstrated by his synthesis of leukotriene A methyl ester (Scheme 42).' ' Ito' l6 has developed a potentiallypowerful method for the stereoselective synthesis of polyols which utilizes an intramolecular bis-silylation-xidation sequence (Scheme 43). Adam'" has adapted the photooxidation of aliylic alcohols into a tita-nium-catalysed epoxy-hydroxylation sequence in which the relative configuration of four contiguous chiral centres can be controlled in a single reaction sequence (Scheme 44).Reagents i Pd(OAc), RNC;ICI; ii KF,KHF, KHCO,; iii Ac,O scbeme43 f -&+ "3 -&-nmf (ref117) major isomer Reagents i O, TPP hv 0°C;ii. 0.05 eq TifOPr'), CH,Cl,. -25°C scheme44 'Is S.Chang N.H. Lec and E.N.Jacobsen,J. Org. Chem. 1993,58,6939. M. Murakami,M. Suginome K.Fujimoto H. Nakamura,P. G.Andersson and Y. Ito,J. Am.Chem. SOC. 1993,115,6487. (n.6.Foran improvement to the Fleming oxidative desilylation reaction see I. Fleming and S. B.D. Winter TetruhedronLett. 1993 34,7287). 'I7 W. Adam and B. Nestler Angew. Chem. lnt. Ed. Engf. 1993 32,733. Aliphatic and Alicyclic Chemistry Enantioselective aziridination1'8*1l9 of olefins has been achieved with high levels of asymmetric induction (up to 96% e.e.).Such compounds prove to be. useful synthetic intermediates (Scheme 45). Ts T" I I 63% (94% w.) 82% H COzMe NHTS Reagents i cat. CuOTf PhI=NTs rt; ii HCO,€€ Pd(o) McOH scbem 4s Alkyaes-Tetraethynylmethane (7) a high-carbon monomer whose polymerization could lead to a network homologous to diamond has been readily prepared from a dibromide (Scheme 45) in an eight-step sequence. *' Solid tetraethynylmethane decomposes rapidly at room temperature but a trimethylsilylated precursor could be handled under ambient conditions and an X-ray crystal structure of this material confirms the structure and reveals that bonds from the central C(sp3)to the C(sp) * D.A. Evans M.M.Fad M.T.Bilodeau B. A. Anderson,and D. M. Barnes,J.Am. Chem. Soc.1993,l IS 5328. *I9 Z. Li,K.R.Conscr and E. N.Jacobsen J. Am. Chem. Soc. 1993 115,5326. K.S. Feldman C. M.Kracbei and M.Parvez J. Am. Chem. Soc. 1993 115 3846. 124 P. Quayle atoms of the attached alkynyl units are lengthened by ca. 0.04A over standard values presumably reflecting steric compression at the central carbon. Medium ring and macrocydic acetylenic lactones are readily available (55-90%) from tosylhydrazones of vinylogous lactones upon treatment with NBS in aqueous Bu'OH (Scheme47).'" Acetylenes are versatile intermediates as demonstrated by synthetic applications of Livinghouse's amidornetallation reaction (Scheme 48)' ''and Takai's metallocydop- ropene functionalizationXz3 (Scheme 49). "HTS (ref 221) Reagents i Bu'OH NBS -10°C; ii NaHSO, 55°C Scheme 47 Reagents i TaCI, Zn;ii py THF; iii RCHO; iv NaOH DME Scheme 49 "' J.R.Mahajan and J.S. Resck 1.Chem. Suc.. Chem. Commun. 1993,1748. 12' P. L. McGrane and T. Livinghouse J. Am. Chem. Soc. 1993 115 11485. lZ3 M.E.Maier. B.-U. Hailer R. Stumpf and H. Fisher SYNLETT 1993,863. Aliphatic and Alicyclic Chemistry Enolrrte Aldoi and Related Reactioa-CoIlum '24 has demonstrated that the readily available hindered amide base (8) enolizes ketones with very high levels of E 2 selectivity (Scheme 50). Use of manganese'. *' and zinc'26 enolates in selective alkylation reactions has been amply demonstrated; asymmetric deprotonations and alkyhtions have found synthetic applications; lZ7 asymmetric protonation of thioi ester enolates has been reported128 to proceed with high levels of asymmetric induction future developments in this area are eagerly awaited.OTMS (AdhNLi + (ref 124) (8) Ad = Z-ada~~~~tyl E:Z 50 1 Reagents i TMSCL THF -20"C Scheme 50 Evans-type methodology is now commonplace for the synthesis of syn aldol products of high diastereoisomeric and enantiomeric purity. 29 Note however that there may be substrate control of the sense of induction as in the case of a,or,a-!-trifluoroketones, which afford 'non-Evans' syn aldol products (Scheme 5 1).' '* Lf Pr'" Reagents i Bu,BOTf PriNEt; ii 4-cyclobcxykrotonaldehyde; iii CF,CHU Scheme 51 ''* K. Sakuma J. H. Gilchrist F.E. Romesberg C. E. Cajthaml and D. B. Collum Tetrahedron Lett. 1993 34 5213.M.T. Reetz and H. Haning Tetrahedron Lett. 1993 34 7395. U. Groth T. Huhn and N. Richer Liebigs Ann. Cksm. 1993 49. A. J. Edwards,S. Hockey F.S. Mair P. R.Raithby R. Snaith and N. S. Simpkins,J.Org.Chem. 1993.58 6942; M. Sobukawa and K. Koja Tetrahedron Lett. 1993,34,5101; D. MiIne and P.J. Murphy J. Chem. Soc. Chern. Commun. 1993 884; Y. Hasegawa H. Kawasaki and K.Koga Tetrahedron Lett. 1993.34 1963. C. Fehr I. Stempf and J. Galindo Angew. Chem. Int. Ed. Engl. 1993 32 1043. lt9 B.D. Dorsey,K. J. Plzak and R.G. Ball Tetrahedron Lert. 1993 34 1851. K.Iseki S. Oisbi T.Taguchi and Y.Kobayashi. Tetrahedron Left. 1993 34,8147. 13' 126 P. Quuyie Subtle changes to the chiral auxiliary and of additives in the reaction can dso affect dramatically the stereochemical course of these reactions (Scheme 52).Reagents i TiCI, RCHO; ii Bu,BOTf RCHO Scheme 52 Evans132has shown that Z enolates derived from fl-hydroxy ketones undergo anti Felkin aldol reactions with high levels of double diastereodifferentiation (Scheme53). Bu' ,But i 156% Bu; ,Bu' _-(ref 133) Reagents i PhBCI, PriNEt CH2Cl, -7% "C scheme 53 Titanium enolates derived from glycine are observed to undergo aldoi reactions133 (presumablyoia a boat-type transition state) with high anti selectivity (up to >99 1 13' T.-H. Yan,C.-W. Tan,H.-C. Lee. H.-C. Lo and T.-Y. Huang. J. Am. Chem. Sm. 1993 115.2613. 13' D.A. Evans and M.A.Calter Telrahedron Lett. 1993 34,6871. 133 S. Kanemasa T.Mori and A.Tatsukawa Tetrahedron Lert. 1993 34,8293. Aliphatic and Alicyclic Chemistry (R4= CH2ph RS= H; >99 :1 d.e.) d.e.) (Scheme 54). In a related area intense interest has focused upon the Mukaiyama reaction,’34-* 35 with particular emphasis on the development of new catalyst systems (Scheme 55) and on synthetic applications of ally1 metat speciesi37(Scheme 56). OBIl OTBDMS -‘ UBn (84% dr) +y-CO*Me H UH (ref 135) Reagents i 3 mot *A LiCIO,. CH,CI, -30°C scheme 55 OH PH SDBU~ Ph (9S%C*.) h-\ (ref 138) Reagents i SnCI, CH,CI,; ii. RCHO; iii. I :1 (R)-BINAP-Ti(OPr’) scheme56 Realization that readiIy available BINOL-derived catalysts impart high levels of asymmetric induction in these reactions represents a major advance.’ ”The observa-tion that aIlyl stannanes undergo highly chemoselective alkylations (al-dehydes > ketones acid chlorides) in the presence of protic acids (2 M HCI) is also of some practical significance (Scheme 571.’ 39 The ene reaction especially when 13‘ K.Mikitmi and S. Matsukawua J. Am. Chrm. Soc. 1993 115 7039. ’” M.Reetz and D.N.A. Fox,Trrrctbdr4m Left.. 1993,34 I 1 19. K.Mikarni M. Terada. and T. Nakai J. Chrm. Soc. Chem. Commun. 1993 343. ‘37 A.H. McNeill and E.J. Thomas. Terrahrdrcm Lett. 1993 34,1569. IJnG.Keck. K.H. Tarbet. and L.S. Geraci J. Am. Chrm. Sw. 1993 115 8467. 13’ A. Yanagisawa H. Inoue M. Morodome. and H. Yamamoto J. Am. Chrm. SIX’..1993. IfS. 10356. 128 P. Quayle 0 (ref 139) Rcsgcnts i. HCI. THF.20°C scheme 57 conducted in a chelation-controlled mode has proven to be highly effective for the creation of up to three contiguous chiral centres in acyclic examples (Scheme 58).I4O EnantioseIective Ref~rrnatsky'~' and nitro-aldol reactions142 have been reported; and copper'44 homoenolates continue to be developed as useful synthetic reagents as do a-and b-heterQsubstituted organolithium ~eagents.'~' 1,7-Asyrnmetric induction has been observed in the reduction of 4-ketoalkylboronates (Scheme 59).146 Reagents i. SnCI,. -8 'C scheme 58 Reagents i. BH,.SMe,. O'C ii. NaOHtaq). H,02 Scheme 59 Radical Reactions.-The use of free radicals for the construction of carbon-carbon bonds continues to attract attention (Scheme A particularly interesting observationthis year is that scaIernic r-sulfinyIenones undergo conjugate addition with t 40 T.Nakamura.K.Tanino. and I. Kuwajima. Tetrahedron Lett.. 1993,34,7591; T. Nakamura. K.Tanino and I. Kuwajima. Tetrahedron Lerr.. 1993 34. 477; K. Mikarni and S.-i. Sakuda J. Chem. SOC. Chem. Commua. 1993. 710. 141 K.Soai. A. Oshio. and T. Saito. J. Chem. SOC..Chem. Commun.. 1993.121 Y.Yamamoto. M.Naito. Y. Uozumi. and T. Hayashi. Terrahedron Letr.-1993.34. 1468. t 41 H.Sasai. T.Suzuki. N.Itoh. S.Arai. and M.Shibasaki. Terrohedron Lerr.. 1993.34.2657 P.Wipf and S. Lim. J. Chem. Soc.. Chem. Commun.. 1993. 1654. t 43 R. F. W. Jackson and A. B.Rettic. Tetrahedron Lert.. 1993. 34.2985. I44 1. Ryu. K.Matsurnoto. Y.Kamcyarna. M.Ando. N.Kusumoto. A. Ogawa. N.Kamk. S. Murai. and Sonada. J. Am.Chem Soc.. 1993. 115. 12330. t45 3. Almcna. F.Foubelo.and M. Yus. Tetrahedron Lett.. 1993.34.1645 A. F.Burchat. J. M. Chong,and S. B. Park. Tetrabdrorr Lett.. 1993.34. 51 A. Guijarro and M.Yus TptrahedronLert. 1993.34. 3487; R. E. Gawky and Q. 2hang.J. Am. Ckenr. Sor.. 1993.115.7515 H. J. Rcich and R.R. Dykstra. Angew. Chem.. hr. €4.€Jig!.. 19!93.32,1459 W.H.Pearson. A. C. Lindbcck. and J. W. Kampf. f.Am. Chem. Sm.. 1993. 115.1521. 146 G.A. Molander and K.L. 3obbitt. J. Am. Cheni. Soc.. 1993. 115. 7517. 14-A. G. Myers. D. Y.Gin. and D.H.Rogers. J. Anr. Cheni. SOC.. 1993. 115. 2036 Aliphatic and Alicyclic Chemistry 129 (ref 147) Reagents i Bu,SnH BEt, 0°C; ii KF MeOH Scheme 60 carbon-centred radicals in a highly stereoselective fashion in the presence of bidentate Lewis acids (Scheme 61).14* The stereoselective functionalization of a-functionalized 50 radicals has also come under further in~estigation.'~'~' A potentially useful observation by AlperLslsuggests that carbon radicals may be trapped by carbon monoxide albeit at high pressure to afford carboxyl-containing products (Scheme 62). Reagents i TiC1,(OPr')2,CH,CI, 0°C; ii BR Scheme 61 d Reagents i CO (6OOpsi) OX Mn(OAc),-2H2O Scheme 62 14' T. Toru,Y. Watanabe M. Tasnaka and Y. Ueno J. Am. Chem. SOC. 1993 115,10464. 149 W.Damm J. Dickhaut F. Wellerich and 3. Giese Terrohedron Lett. 1993,34,431; C.Ferreri M. Ballesrri and C. Chatgilialoglu Tetrahedron Lelr. 1993 34,5147. 15' e.g.D. P.Curran and S.Sun Terrahedron Leu. 1993,34,6181;3.Giese W.Darnm F. Wetterich H.-G. Zeltz J. Rancourt and Y. Guindon Terrohedron Lerr. 1993 34,5885. 1. Ryu and H. Alper J. Am. Chem. Soc. 1993,115,7543. 130 P. Quayle Reductha-The use of oxazaboriIidine-derived reducing agents' 52 fur ketone reduction provides rapid access to a variety of functionalized alcohols with a predictable sense of induction (Scheme 63). Lithium aminoborohydrides' 53 have 0 i (sa%e+.) I (ref 152) I OH Reagents i. BH,-THF 25 T,cat Scheme 63 proved to be highly selective reducing agents. Williams'54 has developed a highly diastereoselective synthesis of syn 1,2-amino aIcohols from the corresponding oximes (Scheme 64). Matsuki has demonstrated that meso anhydrides may be desymrnetrized (ref 154) Reagents i 5 eq TABH CH,CO,H CH,CN 35'C scheme 64 by reduction with the LAH-EtOH-BINAL-H complex to afford lactones with high optical (84 to 95% e.e.1 (Scheme 65).EvanslS6 has developed a chiral samarium catalyst for the promotion of asymmetric Meerwein-Ponndorf-Verley reductions; high Ievels of induction (usually in excess of 97% ex.) are obtained for reduction of aryl alkyl ketones (Scheme 66). C. Boim and M.Feldcr TetrahedronLoft,,1993,34,6041; G.J. Quallich and T. M. Woodall Tefruhedron Leu. 1993 34 4145. J.C. Fuller E. L. Stageland C.T. Goralski and B. Singaram Zetrukedron Lett. 1993 34,257 Is* D. R. Williams M. H. Usterhout and J. P. Reddy Tetrahedron Lett. 1993 34 3271. lS5 K. Matsuki H.Inoue and M.Takeda Tetrahedron Left.,1993 34 1167. IJ6D.A. Evans S.C. Nelson M. R.Gagnc and A. R. Muci J. Am. Chem. Snc. fW3 IIS 9800. Aliphatic and Aficycfic Chemistry w BnNKNBn BnN NBn [ref 155) 75% (90%e.e.1 0 Reagents I (RkBINAL-H -78°C 10 rt Scheme 45 (ref 156) r Reagents i Me,CHOH 5% cat scheme 56 Asymmetric Hydrogenation and Related Reactions-Significdn t advances this year indude the use of the DUPHOS Iigand system (3)in conjunction with rhodium(1)for the enantioselective reduction (typically >99% e.e.) of dehydroamino acids (Scheme 67).157Buchwald158has developeda titanium catalyst for the asymmetric reduction of 4c02R (ref 157) R2 NHCOR' P2= Reagents i cat [ICOD)Rh(P,)]OTf H Scheme 67 trisubstituted olefins { >92% e.e.1.The synthesis and exploitation of novel phosphine Iigands continues to be fashionable.'59 BrownI6" has shown that the hybrid phosphine-isoquinoline ligand system (10) can be effectively employed in the asymmetric hydroboration' 6' of simple olefins (Scheme 681. Is' M.J. Burk,J. E. Feaster W. A. Nugent and R. L. Harlow J. Am. Chrm. Sric. 1993 115 I0 125. Is" R.D. Broene and S. L. Buchwald J. Am. Chem. Soc. 1993 115 2569. H. Brisset Y. Gourdel P. Pellon and M. Le Corre Trtruhedrnn Lett. t993 34,4523. lLr' J. M.Brown. D. I. Hulmes and T. P.Layzell 1.Chem. Soc. Chrm. Commun. 1993 1673. la' N. Sakai S.Mano K. Nozaki and H. Takaya J. Am. Chcm. Soc. 1993 115 7033. 132 P. Quayb + Rh(COD)(acac) + TMSOTf -[(quinoline)Rh(COD>l' CF3S03-catalyst (ref 150) OH I Reagents i Catalyst catechol borane; ii NaOH H,O Scheme 68 In a rather novel departure -asymmetric catalyst poisoning -Fallerls2 has demonstrated that hydrogenation of racemic cyclohexene-1-01 with racemic RuCl,(BINAPJDMF in the presence of (lR,2S)-ephedrine affords the alcohol (11) with high levels of induction (93% e.e.) at 72% conversion (Scheme 69).Reagents i H, (R)-Ru(BINAP) { -)-(1R,2S)-ephedrine2 Scheme 59 Pot Pourri.-Readily available scalemic a-epoxy alcohols,163 (hydroxymethy1)azi- ridine~,~~~ and a$-unsaturated epoxides' 65 continue to find novel uses in synthesis (Scheme 701 as do the now-fashionable oxidizing agents dialkyl dioxiranes166 and TPAP167(Scheme 71). The preparation of optically pure B-amino acids is presently an area of much methodologicaI interest.A particularly ready entry16* into this class of compounds utilizes an asymmetric conjugate addition ofhomochiral lithium arnides to or,fi-unsaturated carboxylic acid derivatives as outlined in Scheme 72. Finally a fascinating report by Yarnamotols9 details the preparation of stable Lewis acid complexes of reactive aldehydes using highly hindered aluminium alkoxide complexes. 162 J. W. Faller and M. Tokunaga Tetrahedron Lett. 1993,34,7359. '63 M.Poch M. Alcon A. Moyano M.A. Percas and A. Riera Tetrahedron Lett. 1993,34 7781. 16* T. Kawabata Y. Kiryu Y. Sugiura and K. Fuji Tetrahedron Lett. 1993,34 5127. 16s M. Miyashita K. Yoshihara K. Kawamine M. Hoshino and H. Irie Tetrahedron Lett.1993,34,6285. 166 R. Curci L. D'Accolti A. Detomaso C. Fusco K. Takeuchi Y. Ohga P. E. Eaton and Y.C. Yip Tetrahedron Lett. 1993,34 4559. 16' K. R. Guertin and A. S. Kende Tetrahedron Lett. 1993,114,5639. N. Asao N. Tsuda and Y. Yarnamoto J. Chem. Soc. Chem. Cornmun. 1993,1660. K.Maruoke A. B. Conqepcion,N. Murase M. Oishi,N. Hirayama,and H. Yamamoto J. Am. Chem.Soc. 1993 115 3943. A1iphatic and Alicycl ic Chemistry 13? (ref 163) TS I NHBOC HO (ref 164) OH (ref 165) Reagents i AlMe, H,O; -30 "C Scheme 70 (ref 164) (ref 167) Reagents i cat. TPAP NMO CH,CN Scheme 71 (ref 168) Scheme 72 The reaction ofsuch species with a variety of nudeophiles is also disclosed (Scheme 73). 3 Alicyclk Chemistry Cyciopropana-Keck' 70 has developed a facile synthesis of vinyl cyclopropanes (12) which themselves are useful synthetic intermediates (Scheme 74).CohenI7 has shown G. E.Keck and S.D. Tonnies Tetrahedron Lett. 1993,34 4607. C.A. Shook,M. L.Romberger S.-H.Jung M. Xiao J. P.Sherbine,B. Zhang F.-T. Lin and T. Cohen J. Am. Chem. Soc. 1993,115 10754. 134 P.Quayle R (ref 170) Reagents i TBSOTf CH,C12 0°C; ii KF,DMSO 18-C-6 scheme 74 that the cyclopropyl sulfides (I3) suffer sequential single-electron reduction alkyla- tion and Peterson olefination to generate the methylene cydopropanes rearrange- ment of which affords a general route to hydrazaazulenes (Scheme 75). Rather Reagents i e- CH,CH=CHCHO; ii KOBu'; iii 180°C scheme 75 unexpectedly,lf2 treatment of cqhnsaturated aldehydes with CrC1,-DMF complex provides a general synthesis of cyclopropanols (Scheme 76).Hoffmann"' has described a rare example of nucleophilic attack at the internal position of a Ir-allylpalfadium complex. Reaction of the complex (14) with a variety of ketone or ester enolates in the presence of TMEDA affords the cyclopropanes (15) in good isolated yields (Scheme 77). The generality of this reaction has yet to be established but it adds a further dimension to the reactivity of this most investigated class of organometallic reagent. Backvall' 74 has demonstrated high site selectivity in the cyclopropanation of 2-phenylsulfonyl-l,3-dieneswith nucleophilic and electrophilic cyclopropanating 172 D.Mongomery K.Reynolds and P. Stevenson J. Chem. Soc. Chem. Commun. 1993 363. A. Wilde A.R. Otte and H. M. R.Hohann J. Chem. Sac. Chem. Commun. 1993,515. J.-E. Backvall C. Liifstrom S. K. Juntuncn and M. Mattson Tetrahedron Lett. 1993 34,2007. Aliphatic and Alicyclic Chemistry 135 (ref 172) H Reagents i CrCl, DMF Reagents i LDA TMEDA 70°C scheme 77 agents; intramolecular cyclopropanations of iodonium ylides' ''have been utilized in the synthesis of a vitamin D ring-A synthon. Enantioselective rhodium-mediated cyclopropanation reactions have again come under much scrutiny. 76 Lee' 77 has developed a simple synthesis of functionalized vinylcyclopropanes which serve as precursors to cyclopentenones and furans (Scheme 78).Normant"* has utilized a \ EWG Reagents i PPh, TMSOTI THF 40"C;ii Bu"Li; iii CH,CH-EWG scbemtt8 metalla-Claisen rearrangement in the stereoselective elaboration of cyclopropanes (Scheme 79).A biomimetic synthesis' 79 of cyclopropane-containing eicosanoids utilized an intramolecular 5,2' substitution reaction of an allylic epoxide (Scheme80). Cyclobutanes-The synthesis ofthe tetraethynylcyclobutadienecomplex (16) has been R.M. Moriarty J. Kim and L. Guto Tetrahedron Lett. 1993,34 4129. M.P.Doyle W.R. Winchester J.A. Hoom U.1. Lynch S. H. Simonscn and R.Ghosh J. Am. Chern. Soc. 1994 115,9968. I" P.H. Lee,J.S. Kim,Y.C.Kim,and S. Kim Tetruhedron Lett. 1993,34,7583. If*D.&rubcn. I. Marek J.-F. Normant and N.Platzer Tetruhedron Lett. 1993.31 7575. J. D.White and M.S.Jenscn J. Am. Chem. SOC.,€993,115,2970. 134 P. Quayle (ref 179) Reagents t SnCI, MeNO, 0°C Scheme 80 (ref 180) described."* LiebskindIB' has developed a versatile route to the bisquaryl system (17) utilizing a Pd/Cu homocoupling procedure (Scheme 81). Organornetallic ap- proaches"' to cyclobutane synthesis have featured heavily this year as outlined in Scheme 82. Corey has described a novel samarium-mediated aldoI-type reaction in Reagents i,5% PdCIBn(PPh,), MeCN 50 "C Scheme 81 Reagents i Cp,ZrCl, BuLi BF,-OEt, -78°C Scheme 82 the synthesis of ( f )-paeoniflorigenin (Scheme 83); similarly Fuk~moto'~~ has *" U.H.F. Bunz and V. Enkelmann Angew. Chem. Int. Ed. Engl. 1993 32,1653. 18' L.S. Liebeskind M. S. Yu,R.H.Yu J.Wang and K.S. Hagen J. Am. Chem. SOC. 1993,115,9048. H. Ito T. Taguchi and Y. Hanzawa TetrahedronLett. 1993,34,7639; M. Hojo K. Tornita Y.Hirohara and A. Hosomi,Tetrahedron Lett. 1993,34,8123; B. M.Trost K. Imi and A. F. Indolese. J. Am. Chem. Soc. 1993,115 8831; B. M. Trost M.Yanai and K.Hoogsteen J. Am. Chem. SOC. 1993 115,5294; S. Kobbing and G. Raabe Chem. Ber. 1993 126 1849. E. J. Corey and Y.-J. Wu J. Am. Chem. Soc. 1993 115 8871. M. Ihara T. Taniguchi K. Makita M. Takano M. Ohnishi,N. Taniguchi,K. Fukumoto,and C. Kabuto J. Am. Chem. Soc. 1993 115 8107. Aliphatic and Alicyclic Chemistry OTIPS (ref 183) Reagents i SmI, THF -45°C Scheme 83 disclosed details of a tandem intramolecular Michael-Aldol reaction fur the synthesis of polycyclic cyclobutanes (Scheme 84).Reagents i TBDMSOTf NEt Scheme 84 [2 + 21-Cycloaddition strategiesls5-' " ha ve been employed in the synthesis of a variety of novel cydobutane systems (Scheme 85). The synthetic utility of the (ref 185) Reagents i 80°C; ii,hv Scheme 85 cydobutane ring system in natural product synthesis has been nicely exemplified by Crirnrnins'" in his synthesis of ( k)-bilobalide (Scheme 86). Cyc1opentanes.-The synthesis of cyclopentanes (and hexanes) from sugar derivatives A. Padwa M. A. Filipkowski M. Meske S.H. Watterson and Z. Ni J. Am. Chem. Soc. 1993,115,3775. F. Jin Y. Xu and W. Huang 3. Chem. Soc. Chem. Commun. 1993 814. W. G. Hollis W. C. Lappenbusch K. A. Everberg,and C. M. Woleben,TetrahedronLett. I993,34,7517.M.T. Crimrnins D.K. lung;and J.L. Gray J. Am. Chem. Soc. 1993 115 3146. 138 P. Qucryle OH Scheme 86 has been exhaustively reviewed by Ferrier.I8’ In keeping with recent trends radical 96 and radical-ani~n-based’~’ approaches to functionalized cyclopen- tanes have again been the subject of intense methodologicaI investigation (Scheme 87); the use of Mn3’ for the generation of rnal~nate-typel~~ radicals provides a useful alternative to more standard methods of radical initiation. In related studies cyclization of radical cationsf 99 provides a direct entry to spirocyclic systems. A novel two-fold addition-rearrangement reaction of vinyl anions to squarate esters generates tetracyclic cyclopentanoids in a single reaction sequence (Scheme 88).*’* A variety of organometallic-based strategies2*‘ have also emerged for the preparation of functionalized cyclopentanes (Scheme 89).Most notable amongst these is the Kn~cheI~~~-Normant~*~ cyclization of w-oIefinic organozinc reagents (Scheme 90),a zirconium-mediatedringcontraction of carbohydrate derivatives (Scheme 91 and a titanocene-catalysed conversion of eneynes into bicyclic cyclopentenones (Scheme 92).205The latter provides a useful alternative to the more common Pauson-Khand 1139 R.J. Ferrier and S. Middleton Chem. Rev. 1993,93,2779. 190 D.L,J. Clive and H. W. Manning J. Chem. Soc. Chem. Commun. 1993,666. 191 J. Fidalgo L. Castedo and D. Dominguez Tetrahedron Lett. I993,34 7317. 192 Y.-J. Chen C.-M. Chen and W.-Y. Lin Tetrahedron Lett.1993,34 2961. 193 V. H.Rawal V. Krishnamurthy and A. Fabre Tetrahedron Lett. 1993,34 2899. 19A C.-K. Shan C.-Y. Shen T.-S. Jean R.-T.Chiu,and W.-H. Tseng TetrahedronLett. 1993,34,7641;K.S. Feldman H. M. Berven and P. H. Weinreb J. Am. Chem. SOC. 1993,115,11 364;J. W.Grissom T.L. Calkins and M.Egan J. Am. Chem. Soc. 1993,115,11 744. 19s F.-H. Wartenberg H. Junga and S. Blechert Tetrahedron Lerr. I993,34 5251. 196 J. E.Brumwell,N. S. Simpkins and N. K. Terrett Tetrahedron Lett. 1993,34,1215;D. F.Taker Y.Wang and S. J. Stacel Tetrahedron Lett. 1993,34,6209. 197 J. M.Aurrecoechea and A. Fernandez-Acebes Tetrahedron Lett. 1993,34,549;T.Gilhann Tetrahedron Lett. 1993,34,607;S. Arseniyadis D.V. Yashunsky M.Dorado R.B. Alves E.Toromanoff,L.Toupet and P. Poitier Tetrahedron Lett. 1993,34 4927. 198 J. Cossy and A. Bouzide Tetrahedron Lett. 1993,34 5583. I99 J. Cossy and A. Bouzide J. Chem. SOC.,Chem. Commun. 1993,1218. 200 J T. Negri T. Monvick J. Doyon P.D. Wilson E.R. Hickey and L.A. Paquette J. Am. Chem. Soc. 1993,115,12 189. 20I B.A. Anderson J. Bao T. A. BrandvoId C.A. Chatlener W. D. Wulff Y.-C. Wu Xu and A. L. Rhcingold J. Am. Chem. Soc. 1993,115 10671; M.Yarnaguchi M. Sehata A. Hayashi and M. Hirama J. Chem. Soc. Chem. Commun. 1993,1708;3. M.Trost and Y.Shi J. Am. Chem.Soc. 1993,115,9421;K. Takeda M. Fujisawa T. Makino E. Yoshii and K.Yamaguchi J. Am. Chem. Soc. 1993 115,9351; T.J.Katz A. M. Gilbert M. E. Huttenloch G. Min-Min and H. H. Brintzinger Tetrahedron Lett.1993,34,3551; H. Pellissier A. Tubul and M. SanteIli Tetrahedron Lert. 1993,34 827;M.Toyota Y.Nishikawa K. Motoki N.Yashida and K. Fukumoto Tetrahedron Lett. 1993,34,6099;X.-M. Wu K.Funakoshi and K. Sakai Tetrahedron Lett. 1993,34 5927; H.-J. Knoller and R. Graf Tetrahedron Lett. 1993,34,4765. 202 H. Stadtmiiller R.Lentz C. E. Tucker T. Stiidemann W.Darner and P. Knochel J. Am. Chem. Soc. 1993,115,7027. 203 C.Meyer I. Marek G. Courternanche and J.-F. Normant Tetrahedron Lett. 1993 34 6053;H. Stadmiiller C. E. Tucker A. Vaupel and P. Knochel Tetrahedron Lett. 1993,34 791 1. 204 H. Ito Y. Motoki T. Taguchi and Y.Hanzawa J. Am. Chem. Soc. 1993,115,8835. 20 5 S.E.Berk R.B. Grossman and S.L. Buchwald 1.Am. Chem. Soc. 1993 115,4912. Aliphatic and Alicyck Chemistry km@ (ref 193) OH 3:1 Reagents i Bu,SnH AIBN srbeme87 P.Quayle i-4*4 eSipi3 + 97% 0 0 0 (ref 201) 1 97% -'s PMBO PMBO \ OT3DMS Reagents i TiCl, -78 "C;ii Pd,(dba), CHCL, KOAc BDEDA Scheme 89 Reagents i Zn Et,O; ii E' Scheme 90 i ii (ref 204) Reagents i 'Cp,Zr'; ii BF,-UEt Scheme 91 (ref 205) Reagents i 'Cp,Ti',R"C; ii H,Ot Scheme 92 reaction which has aIso enjoyed continuing interest .*" 5-Endo-dig-cyclizationzo7 of acetylenic ethers promisesto provide a rapid entry into '06 S.-e. Yoo S.-H. Lee,N.Jeong and I. Cho Tetrahedron Letr. 1993,34,3435; M. E. Kraft I. L. Scott S.H. Romero S. Feibelmann and C. E. Van Pelt J. Am.Chem. SOC. 1993,115,7199.207 R. L. Funk G. L. Bolton K. M. Brummond K.E. Ellstead and J. B. Stallman J. Am. Chem. SOC. 1993 1IS,7023. Aliphatic and Alicyclic Chemistry a variety of cyclopentane derivatives as does the Enders''' diastereoselective intramolecular conjugate addition of SAMP-RAMP enolates to a,fl-unsaturated esters. FinaIly,'09 thermal reaction of a,w-bis-diazoketones affords a general synthetic route to both cyclohexenones and cyclopentenone derivatives (Scheme 93). (ref 209) %heme 93 Cyc1ohexanes.-The use of a-santonin in natural product synthesis has been re-viewed.210The 65th birthday ofthe Dieh-Alder reaction was celebrated in style with a review*' on recent developments and the numerous examples of synthetic applica- tions of existing and novel diene-dienophile partners (Figure 1).2' The use of tandem intramolecular Diels-Alder reactions (TIMDA) is a potentially powerful strategy if the timing of sequential cycloadditions can be contrdled.Synthetic applications of this process have appeared this year which shows that this is achievable (Scheme 94)'l 3,2'4 The development of effective catalysts for asymmetric intermolecular Diels-Alder reactions continues to be a major preoccupation2'5*216 and some examples are illustrated in Scheme 95. Of particular interest are the reports of and Sanders;2 the latter is concerned with the development of chemically engineered enzyme mimics which enhance both the rate of Diels-Alder reactions and promote D. Enders H.J. Scherer and J. Runsink Chem.Ber. 1993 126 1929. '09 S.Ohira M. Moritani T. Ida and M. Yamato J. Chem. Soc. Chem. Commun. 1993,1299; K.Nakatani K. Takada Y.Odagaki and S. Ism J. Chem. Soc. Chem. Commun. 1993 556. 'lo A. K. Bancjee W. J. Vera and N. C. Gonzalez Tetrahedron 1993 49 4761. 211 K. Krohn Angew. Chem. lnt. Ed. Engl. 1993 32 1582. '"(a)H. J. Reich I. L. Reich K. E. Yelm J. E. Holladay and D. Gschneider J. Am,Chem. SOC. 1993,115 6625; (bf B.L. Williamson P.J. Stang and A. M. Arif J. Am. Chem. Soc. 1993,115,2590; (c) M. E.Jung, C.N.Zimmerman C.T. Lowen and S.I. Khan Tetrahedron Lett. 1993,34,4453; (d)M. Nakagawa Y. Torisawa T. Hosaka K.Tanabe T. Da-te K Okamura and T.Hino Tetrahedron Lett. 1993,34,4543; (e)V. H. Rawal C. Michoud and R.F. Monstel J. Am. Chem. Soc. 1993,115,3030; u> M.C. Clasby D. Craig and A. Marsh Angew.Chem. Inr. Ed. Engl. 1993,32,144; @) Y.-F. Lu and A. G. FalIis Tetrahedron Lett. 1993,34,3367; (h)D. A. Singleton K.Kim and J. P. Martinez Tetrahedron Lett. 1993,34,3071; (i) J. Barluenga F. Aznar,C. Valdes A Martin S. Garcia-Granda and E. Martin J. Am. Chem.SOC. 1993 115,4403;0)J.-P. Duldre V. Agati and R. Faure J Chem. Soc. Chem. Commun. 1993 270; (k) J. E. Kerrigan P.G. McDougal and D. VanDerver TerralredronLett. 1993 34 8055; (1) J. Martynow M. Dimitroff and A.G. FaIlis Tetrahedron Lett. 1993 34 8201; (m)J.P. Konopelski and R.A. Kasar Tetrahedron Len. 1993,34,4587; (n)A. Kambuchi N. Miyaura and A. Suzuki. Tetrahedron Lett. 1993 34,4827. 2'3 I. E. Marko P. Seres G. R. Evans and T. M.Swarbick Tetrahedron Lett.1993 34 7305. D. R. Goldberg J. A. Hansen and R.J. Giguere Tetrahedron Lett. €993 34 8003. 'I5 E.J. Corey and Z. E.Wang Tetrahedron Lett. 1993 34,4001. 'Is K. Ishihara 0. Gao and H. Yamamoto Tetrahedron Lett. 1993 34 6917. 'I7 D.C. Braddock 3. M. Brown and P.Guiry J. Cfiem.Soc. Chem. Commun. 1993 1244. 'I8 C. J. Walter H. L.Anderson and J. K. Saunders J. Chem. Soc. Chem. Commun. 1993,458. 142 P. Qtcayle (ref 212) Figure I (ref 21 4) Reagents i BF,-OBt, CH,CI, 0°C exo-edu selectivity {Scheme 96). Photo-induced Diels-Alder reactions are also reported to be em elective.^'^ Free radical reactions have been exploited to good effect in the synthesisofa range of cyclohexane-contining systems (Scheme 97),2’* as have a variety of tandem Michael-typ reactions22* (Scheme 98).Harman222 has developed a novel dearomatization procedure via the intermediacy of osmium(rI)(q2-aryl)complexes (Scheme 99). This ‘19 B. Pandey and P. V. Dalvi Angew. Chem. Inr. Ed. Engl. 1993 32. 1612. D. L.J. Clivt and M.H.D. Postcma J. Chem. Soc. Chem. Commun. 1993,429. ’”C. Kuroda Y. Ohnishi and J.Y. Satoh,Tetrahedron Lett. f993,34 2613. 222 J. Gonzalez M. %bat and W. D. Harman J. Am. Chem. Sw. 1993 115,8857. 143 0+ 23 OO 0 (ref2I5) (ref 216) 0+Me++ OMe -.Q‘ +q0Me(d218) 0 S OMe 0 OMe 94 6 (BF-@E4:% (EJC13) tZ) Reagents i Lewis Acid CH,CI Schem% li SePh Reagents i Ph,SnH BEt, ‘air’ scbem97 0 8:l Reagents i TiCI, CHI,CI scbeme98 144 P.Quayle 0 (ref 222) 3 0 Reagents i TBSOTf PriNEt MeCN Scheme 99 methodology could have many synthetic applications; further developments are anticipated in this area. Medium Rings.-The synthesis of medium-sized ring systems has recently been extensively reviewed223 as have approaches to the highly functionalized enediyne family of antitumour agents." 223 C. J. Roxburgh Tetrahedron,1993,49 10 749.

ISSN:0069-3030    

DOI:10.1039/OC9939000105

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

6 Aromatic Compounds By A. P.CHORLTON ZENECA Specialties Hexagon House. Bla~kley,Manchester M9 3DA. UK 1 General and Theoredcal Studim [1,2-13C2]Benzene autornerizes at high temperature to give a 1,2 :1,3:1,4 product ratio of 72 :24 :4. Four plausible mechanisms to explain this have been put forward the 1,Zcarbon shift mechanism; the dyotropic shift mechanism; the benzvalene mechan- ism; and the 1,Zhydrogen shift mechanism. High-level ab Wtiocalculations have been reported that favour the 1,Zhydrogenshift process.' The photochemistry of S and S benzene involves the production of benzvaiene and Dewar benzene respectively. An MC-SCF study of these processes indicatesthat the products of benzene photochemis- try appear to be controiled by the topology of the S,/S Grassing surface.2 The X-ray crystal structure and photoelectron spectrum of 3,3'-bicyclopropnyl (1 one of the four valence isomers of benzene,has been determined.The photoelectron spectrum of (I) can be interpreted in terms of about a 2 :1 mixture of anti and gauche conformers respectively in the gas phase whereas the X-ray crystal structure of (1) is only present in the anti form.3 Zirconocene complexes of the highly strained isomers of benzene I,2,3-cyclohexa-triene (2) and cyclohexen-3-yne (3) have been synthesized? A new multiphoton fragmentation of benzene at 193 nm has been proposed to proceed via the intermediate triplet states and neutral fragments such as C,H,.5 Squires and coworkers have reported values for the heats of formation of 0-,m-,and p-benzynes based on energy-resolved collision-induced dissociation measurements.The CI calculations carried out independently by the groups of Squires and Borden gave good agreement ' K.M.Men and L.T. Scott J. Chem. SOC.,Chem. Cornmun. 1993 412. I. J. Palmer I.N. Ragazos F. Bernardi M. Olivucci and M. A. Robb J. Am.Chem. Soc. 1993 115,673. R. Boese D. Blaser R.Gleiter K. W.Pfeifer W. E.BiIlups and M. M.Haley J. Am. Chem.Soc. 1993,i15 743. 'J. Yin K.A. Abboud and W.M. Jones J. Am Chem. SOC. 1993 115,8859. Y.Mori and T. Kitagawa Bull. Ckem. SUC.Jpn. 1993.66 1043. 145 A. P. Churlton with the experimental results for the heats of formation of o-benzyne but find that the experimental results for m-and p-benzyne are too Photolysis of benzocyc-lobutenedione (4) gives o-benzyne via the intermediacy of the bisketene (5).Exarnin-ation of this process in an argon matrix shows that (5) and (4) can interconvert thermally or photochemically several times before significant photochemical decar- bonylation to o-benzyne occurs.* Evidence has been presented for the presence of a halide-benzyne complex in the gas phase.' The generation of arynes in the gas phase has been reviewed." The role of delocalization in benzene has been the subject of debate; ab initio SCF caIculations have shown that it is misleading tojudge the nature ofdelocalization based on a 0-zpartition.It was therefore conciuded that delocalization effects act to stabilize strongIy symmetric benzene in accord with concepts ofclassical resonance theory.' l Classical valence bond theory has also been applied using quantitative resonance theory (QRT) to access the It-electron transfer in substituted benzenes.These QRT calculations areinagreementwith thoseobtained viaabinitio MO theory." Messmer hascuncluded based on energetic considerations that the phenomenon of resonance in the cIassica1 valence bond sense is best described by a bent-bond model.' The results of these cal-culations indicate that the benzenoid isomer (6)is preferred over the quinoid form (7).14 The structure of 1,3,5-triamino-2,4,6-trinitrubenzene (8) and a number of related compounds have been studied using ab initio Hartree-Fock and local density functional computational methods. These calculations predict a planar structure in accord with an X-ray crystallographic study; this is a contradiction to semiempirical data which predict (8)to be in the boat conformation.The planarity of (8)is thought to be due to hydrogen bonding of the flanking groups.' 'Hall hasargued that when a benzene ring is S.U. Wierschke J.J. Nash and R.R. Squires J. Am.Chem. Soc. 1993,115,11950. ' A. Nicolaides and W.T. Borden J. Am. Chem. Soc. 1993 115 If 951. a T.Mosandl and C. Wentrup J. Org. Chem. 1993,58 747. H.V. Linnert and J. M.Riveros J-Chem. Soc. Chem. Commun. f993,48. R.F.C. Brown and F.W. Eastwood SYNLETT 1993,9. I' E. D.Glending,R. Faust,A. Streitwieser,K. P.C.VoIlhardt,andF. Weinhold,J. Am. Chem.Soc.,1993,115 10952. l2 Y.Pipeng J. Gem. Res. (S) 1993,368. P.A. Schultz and R.P.Messmer J. Am. Chem. Soc. 1993 115 10943. J. M. SchuIman and R.L. Dish J. Am. Ckm. Soc. 1993 115 11 153. K. K. Baldridge and J.S. Siegel J. Am. Chem. Soc. 1993 115 10782. Aromatic Compounds (9) (lo) X = H; Y = H. (111 X = H;Y = Br. (12) X=Br;V=Br. present as an embedded component in a molecule e-g. (9) then the adoption by the benzene ring of the boat form requires the least en erg^.'^ X-Ray crystalIographic and dynamic 'H NMR spectroscopy of 2,3,6,7-tetrab- romo-l,4,5,8-tetramethylnaphthalene(1O)and its bromo derivatives (1I)and (12)show that these compounds have severely distorted naphthalene nuclei in the solid state. In solution this corresponds to conformations that can have an appreciable barrier to conversion(AG*=t 16 Kcal mol- ') which occurs by both rotation and flipping of the peri-substituents.' The rotation of the peri positions in 1-t-butyl-8-fluoronaphthalene has also kn studied by dynamicNMR.The barrier to rotation of the t-butyt group has been calculated'* at AG* 11 8.6 Kcal mol- I. In a similar study the barrier for the E-2 interconversionof atropisomers of naphthyl- 1-sulfones having a methyl group at the 2-position has been measured and found to cover the range 10.6-18.4Kcal mol -'.Low temperature chiral resolution allowed the separation of the two enantiomeric forms and their associated atropisomers.' The restricted rotation in 1&diarylnaphthalenes (13) has been used to probe the interactions between x-stacked dimers of benzenes. The attractiveor repulsiveforces between the benzenes should give rise to a higher or lower energy barrier to rotation respectively.The barrier to rotation was found to increase linearly with the increasing electron-withdrawing capacity of the X and Y groups. No extra increase in the rotation barrier was noted when X = OMe and Y = NO,. These observations point to the domination of polar/lt over charge-transfer effects in the interaction of stacked benzene rings." XY Is G.G. HaH J. Chent. Soc. Perkin Trans.2 1993 1491. *' P.R. Ashton G.R. Brown A.J. Foubister D. R. Smith N. Spencer J. F. Stoddart and D.J. Williams Tetrahedron Lett. f993 34 8333. G.W. Gnbble and E. R. Olson J. Org. Chem. 1993,58 1631. j9 D. Casarini E. Forsti F. Gasparrini L.Lunazzi D. Macciantelli D.Misiti and C. Villani J. Org. Chem. 1993,58 5674. F. Cozzi M. Cinquini R. Annunziata and J. S. Siegel J. Am.Chem. Soc. 1993 115 5330. A. P. Ckorlton The aromaticity or lack of it in c, is a contentious issue. Fowler has put forward qualitative symmetry arguments with evidence from bond lengths and energies and from the addition chemistry of C60,which point to a localized description of the 7~ system in this molecule. Regioselective saturation ofsix double bonds in C, is predicted to give the 48 electron aromatic system (14).” It has been postdated that large polycyclic conjugated rings such as kekulene (15) with an internal cavity may exhibit superaromaticity. A general graph theory of superaromaticity has been developed to analyse this phenomenon.The results of this work indicate that these systems are essentially non-superaromatic.” The ESR spectrum of a non-Kekule polynuclear aromatic has been reported for the first time; trioxytriannufene (15) is a remarkably stable triplet biradi~al.~~ Full characterization of the disjointed non-Kekule singlet hydrocarbon I ,2,4,5-tet-rarnethylenebenzene biradical (17) has been completed.24 Contrary to previous results it has been established by theoretical methods that 1,4-bishomotrupylium cation (18) rather than the cis-8,9-dihydro-l-indenyl cation (19) corresponds to the minimum energy structure. These calculations however are not sensitive enough to confirm the homoaromatic character of (18).” Homoaromaticity has been tentatively ascribed to the stabilization shown by arene oxides on their acid-catalysed aromatization.26 -5 7 2 Preparation of Benzenes from Non-aromatic Precursors The Bergman cydization the thermal rearrangement of conjugated cis-enediynes to P.W. Fowler D. J. ColIins and S. J. Austin J. Chem. Soc. Perkin Trans. 2 1993 275. l2 J. Aihara Bull. Chem. SOC.Jpn. 1993,66,57. 23 G.A. Allinson R. J. Bushby and 3.L. Paillaud J. Am. Chem. SOC. 1993 115 2062. 24 J. H. ReynoIds J. A. Berson,K. K. Kumashiro,J.C. Duchamp K.W. ZiIm J. C. Scaiano A. B. Berinstain A. Rubella and P. Vogel,J. Am. Chem. Soc. 1993,115 8073. ” D. Crerner P. Svensson E. Kraka 2. Konkoti,and P. AhIberg J. Am. Chem. SOC. 1993 115 7457. ’‘ S. Nagaraja Rao R.A. M. O’FerralI S. C. Kelly D. R. Boyd,and R.Agarwal J. Am. Chem.SOC.,1993,115 5458. Aromatic Compounds 1,4-benzenoid diradicals continues to be ofimmense The incorporation of the cis-enediyne in the synthesis of naturally occurring antitumour antibiotics represents the major challenge. This has been achieved by Nicolaou who has reported the first synthesis of ~aIichearnicin.~~-~~ Successful model studies towards the synthesis of dynemicin have also been ~ornpleted.”~~~ Magriotis has developed a tandem Claisen-Bergman strategy fur the stereocontrolled synthesis of tetrahydronaphtha-lenes (Scheme l).32 tO2TIPS Reagents i LHMDS THF,-78“C,TlPSOTf Scheme 1 Grissom has demonstrated that enediynes (20) possessing tethered olefin radicaI acceptors can participate in tandem enediyne-radical cyclizations to yield dihydroben- zindenes (21) (Scheme 2).33-35 Meyers has shown that 1,Qdidehydro[ 1Olannulene (22) undergoes a rapid cydiz- ation to form the biradical 1,5-dehydronaphthalene (23).36In a similar study Toshirna has cyclized the enyne-alIene sulfides (24) and sulfones (25).37*38 27 R.Gleiter and d. Katz AnQew. Chem. Int. Ed. Engl. 1993,32,842. K.C. Nicolaou C. W. Hummtl M.Nakada K. Shibayama E. N.Pitsinas H. Saimoto Y.Mizuno,K. U. Batdenius and A. L. Smith J. Am. Chem. Soc. 1993,115,7625. 29 K. C.Nicolaou Angew. Chem. Inr. Ed. Engi. 1993,32,1377. K. C. Nicolaou W. M. Dai Y,P. Hong,S.C. Tsay K. K. Baldridge and J. S. Siegal J. Am. Chem. SOC. I993,115,7944. 3’ P.A. Wendtr C. K.Zerchtr S. Beckham and E. M. Haubold J.Org. Chem. 1993,58,5867. 32 P.A.Magriotis and K.D. Kim J. Am. Chem. Soc. 1993,115,2972. 33 J. W.Grissom and T. L. CaIkins. 1.Org. Chem. 1993.58 5422. 34 J-W. Grissom,T. L. Calkins and H. A. McMillen J. Org. Chem. 1993,58 6556. 35 J. W. Grissom T. LaCalkins and M. Egan J. Am. Chern. SOC. 1993 115,11 744. 36 A.G.Myers and P. S. Dragovich J. Am. Chem. Soc. 1993,115 115 7021. 37 K.Toshima K. Ohta A. Ohashi T. Nakamura M. Nakata and S. Matsumura J. Chem. SOC.,Chem. Comun, 1993,1525. 38 K. Toshima K. Ohta A. Ohtsuka S. Matsumura and M. Nakata J. Chern. SOC.,Chem. Commun. 1993 1406. A. P. Chorlton Reagents i PhCI cyclohexa-l+diene 19O"C,2.5br (96%) Scheme 2 OH CH&CCHpS OR OR I (24) X = S (25) x = sop This approach has also been utilized by a number of workers to investigate the enyneC3lcumulene cyclization of neocarzinostatin (26) (Scheme 3).39-42 Padwa in an investigation of the decomposition of o-alkynyl substituted aryl diazo ketones (27) has proposed that the intermediate aryl ketene (28) cycIizes in a Meyers-type process to give the diradical (29) which on quenching gives the 8-naphthol (3U).43 The synthesis of benzene rings via Fischer carbene complexes continues to be widely utilized.Wulff and coworkers have carried out an in-depth study into this reactionq4 The results of these experiments suggest that phenol (31) arises from a vinyl carbene cornplexed intermediate (32) and that phenol (33) and cyclopentenedione (34) arise 39 S. W. Scheuplein R.Machinek J. SuEert and R. BNCkner Tetrahedron Lett. 1993,34 6549. 40 T. Takahashi H. Tanaka Y. Hira T. Doi H. Yamada T.Shiraki and Y. Sugiura Angew. Chem. Int. Ed. Engl. 1993,32 1657. 41 M.Tokuda K. Fujiwara T. Gomibuchi and M. Hirama Tetrahedron htt. 1993,34 669. 42 K.-I. Yoshida Y. Minami R Azuma M.Sacki and T. Otani Tetrahedron Lett. I993 34 2637. 43 A. Padwa U. Chiacchio D.J. Fairfax,3. M. Kassir A. Litrico M. A. Scmones and S.L.Xu 1.Org. Chem. 1993,58 6429. 44 B.A. Anderson J. Bao T.A. Brandvold C. A. Challener W.D. Wulff,Y.-C. Xu and A. L. Rheingold J. Am. Chem. Soc. 1993,115 10671. Aromatic Compounds Scheme 3 from a vinyl ketone complexed intermediate (35). The product distribution of these products is discussed with reIation to solvent concentration and nature of metal (Scheme 4).In another study Thomas and coworkers have synthesized metal complexed vinyl ketenes of the type (35) and have shown that their reaction with aIkynes leads to phenols (33) if the R group is eIectron donating whereas if this substituent is electron withdrawing cycIopentenediones (34) are f~rmed?~.~‘ Differentially protected hydroquinone-(tricarbony1)chromium complexes (36)can be prepared directly from alkenyl and alkynyl Fischer carbene complexes by interception with a variety of electrophile~.~~ The first example of bemannulation of alkynes with iron@) carbene complexes has been reported. Furan annulation is a competing process in this reaction.48 The reaction of carbenexhromium complex (37) with isocyanides provides a mild and regiospecific access to aromatic amines Is K.G.Moms S. P. Saberi M. Salter S. E. Thomas M. F. Ward A.M. Z. Slawin and D. J. Williams Tetrahedron,1993 49 5617. 46 K.G.Morris,S. P. Saberi and S.E. Thomas J. Chem. Soc. Chem. Commun. 1993 209. S. Chamberlain W.D.Wulff and B. Bax Tetrahedron,1993,49 5531. ’’ Atta-ur-Rahmann,W. F. K. Schnatter and N. ManoIache J. Am. Chem. Soc. 1993 115 9848. A9 R. Aumann Chem. Bet. 1993,126 1867. A. P.Chorlton OH R2 I t Hi (33) ONrnY-6 R’ Cr(CO) (35) Reagents i R’CZCH; ii RZCECH,CO scheme 4 o-Amino phenols (39) can also be prepared via the photocyclizationof aminocar-bene-chromium complex (40).50 A similar process utilizing the methoxycar-bene-chromium complex (41) furnishes the annulated catechol (42).’ (40)X=NHR (39)X=NHR (41) X=OMe (42)x=o C.A.Medic D. Xu and B.G.Gladstone J. Org. Chem. 1993,58,538. 5r C.A. Medic and W.M.Roberts Tetrahedron Lett. 1993 34,7379. Aromatic Compounds Catechols have also been synthesized by the ruthenium-catalysed reaction of 176-diynes with carbon monoxide. This transformation is unique in that it represents a rare example of catalytic incorporation of carbon monoxide into a diyne. Also it exhibits a new mode of successive incorporation of two molecules of carbon monoxide (Scheme 5).52 ‘)(: E OTBDMS + TBDMSH + CO --E OTBDMS E= COzEt Scheme 5 An alternative regiocontrolled synthesis of substituted catechols has been develop- ed the products from conjugate addition of vinyl copper reagents to cyc-lobutenediones when subjected to thermal rearrangement yield catechols (Scheme OH Scheme 5 @-fS, a similar process addition of stannylquinones to 4-chlorocycIobutenones followed by thermal rearrangement gives substituted naphthoquinones and anthra- quinone~.~~ Liebeskind has developed a general regioselective synthesis of substituted benzocy- clobutenedione monoacetais.These reagents can function as important intermedi- ates in the regioselective synthesis of phenols. 3-Alkylidene-4-allenylcyclobutenes undergo thermal ring expansion to give o-quinodimethanes which upon eiectrocyclic ring closure give benzocyclobutenes (Scheme 7).56 o-Quinodimethanes are of synthetic utility as effective dienes in DieIs-Alder reactions fur the construction of polycycIic aromatics.A number of novel methods have been developed for the generation of o-quinodimethanes (Scheme 7).57-59 Benzyne and benzoquinone have been used effectively as 2n components in Diels-Alder reactions to prepare 1,4-naphthoq~inones.~~~~~ Negishi has developed a ” N. Chatani Y. Fukumoto T. Ida and S. Murai J. Am. Chem. Soc. 1993,115,11 614. ” A. Gurski and L. S. Liebskind J. Am. Chem. SOC. 1993,115,6101. ” J. P.Edwards D.J. Krysan and L.S. Liebeskind J.Am. Chem. Soc. 1993,115,9868. ” J. P.Edwards D.J. Krysan,and L,S. Liebeskind J. Org. Chem. 1993 58 3942. ’’ J-E. Ezcurra and H.W. Moore Tetrahedron Lett. I993,34,6177. 57 S.H. Woo Tetrahedron Lett. 1993,34,7587. ’’ H.Fujihara M. Yak and N.Furukawa J. Org. Chem. 1993,58 5291. 59 G.Kanai N. Miyaura and A. Suzuki Chem. Lett. 1993 845. A. P. Chorlton Reagents i A or hv; ii E*; iii hv scbeme 7 selective synthesis of benzene derivatives via palfadium-catalysed carbometdlation of alkynes (Scheme 8).62 Ph Reagents i R'CECR' 5% PdL, NEt, DMF Scheme 8 The intramolecular Michael-Aldol process has been used in the synthesis of the hexasubstituted aromatic ring present in a key intermediate for the synthesis of pseudopterosin A.63 Naphthopyrans have been synthesized from a 14-membered pdyketide lactone by the intramolecular aldol process.64 Salicylates have been prepared by themolytic ring closure of prop-1-en-1-yI substituted malonates (Scheme 9).65 M.A. Brimble and S.J. Phythia Tetrrihedron Lett. 1993 34 5813. 61 V.I. Hugo,P.W. Snijman ai,d I. R. Green Synth. Commun. 1993 23 577. E.Negishi M.Ay,and T. Sugihara Tetrahedron 1993,49 5471. 63 M.E. Jung and C.S.Siedem J. Am. Chem. Soc. 1993,115 3822. 64 K.Tatsuta Tetrahedron Lett. 1993 34 4961. 65 0.E.O. Homi and L. Hirvela Tetrahedron Lett. 1993,34,6463. Aromatic Compounds Frost has made progress in the identification and removal of impediments to the biocatalytic synthesis of aromatics from gIu~ose.~~ 3 Non-aromatic Compounds from Benzene Precursors Intramolecular anodic oxidation of phenols (43) leads preferentially to spirodienones (44);a competing reaction gives the methanol adduct (45). Swenton has examined the process and has shown that the product ratio is dramatically affected by the olefin structure.67 A versatile route to quinone N-acylimine ketaIs (46) from p-methoxyanil- ides has been developed utilizing anodic oxidative technol~gy.~~.~~ Anodic oxidation of 3,5-dihalogenotyrosines (47) gives a cavernicolin model compound (48).All four possible stereoisomers were formed but this was due to the special characteristics of (48) rather than the method~logy.~~ Similar intramolecular oxidative processes using hypervalent iodine have been effected to obtain the key intermediate (49) in the total and partiaI synthesis of aranorosin (50);the model compound (511 an intermediate towards the synthesis of marine metabolites such as aerothionin has been synthesized by these methods -73 A study of phenolic oxidation using phenyliodonium diacetate has also been carried " K.A. Dell and J. W. Frost,J. Am. Chem. Soc. 1993.115 11 581. 67 J.S. Swenton K. Carpenter Y. Chen M. L. Kerns and G.W. Morrow,J. Org. Chem. 1993.58 3308. J.S. Swenton T. N. Biggs and W. M. CIark J. Org. Chem. 1993 SS 5607. b9 M.Novak,J. S. Hehick N.Oberlies K.S. Rangappa,W. M.Clark and J. S. Swenton,J. Org. Chem.,1993 58 867. '* M. Cavazza,G. Guella L. Nu& F. Pergola N. Biahicrini and F. Pietra J. Chem. Soc. Perkin Trans. 2 1993,3117. 71 A. McKillop L.McLaren R.J. Watson R. J. K. Taylor and N.Lewis TetrahedronLett. 1993,34,5519. '' P. Wipf and Y. Kim J. Org. Chem. 1993,58 1649. 73 M. Kacan D. Koyuncu and A. McKilIop J. Chem. Soc. Perkin Trans. I 1993 1771.'' A. Pclter and S.M. A. Elgendy J. Chem. SOC. Perkin Trans. 1 1993 1891. A. P. Chorlton Microbial oxidation of benzenes to cis-cyclohexa-3,5-diene diols has been used as the key transformation in the synthesis of inositol stereoisomers and deuteriated conduritol derivative^.^^.^^ The bacterial degradation of aromatic compounds has been discussed. ' The mechanism of ceric ion oxidation of naphthalene to naphthoquin-1 +one has been in~estigated.~' This oxidation can also be achieved with hydrogen peroxide catalysed by hexafluoroacetone hydrate. 79 The oxidation ofhydroquinones to quinones can be effected in the solid state with cerric ammonium nitrate.80 Hydroxyaromatics can be oxidatively cleaved with superoxide to aromatic 1,2-dicarboxylic acids." Electrochemical reduction of phthalic acids gives 1,2-dihydrophthalic acids which have been used as diene components in synthesis.82 The reduction of disubstituted naphthalene derivatives by potassium-graphite intercalate C,K has been reported.The C,K-ether system may be an alternative to Birch-type reaction^.'^ Oxazo-line-mediated 1,S-nucleophilic addition to aromatic rings has continued to be utilized by Meyers as in the key step in the synthesis of the phytoalexin lancinilene (Scheme Reagents i (CH,CHCH,SiMe,)Li; ii Me1 Scheme 10 75 H. A.J. Carless K. Busia and U.Z. Oak SYNLETT 1993 672. 76 H.A. J. Carless K. Busia Y. Dove and S. S. MaIik J. Chem. SOC.,Perkin Trans.I. 1993,2505. 77 G. Gottschalk and H.-J. Knackmuss Angew.Chem. In[. Ed. Engl. 1993,32,1398. " M.V.Bhatt and M. Periasamy J. Chem. SOC.,Perkin Trans.2 1993,1811. 79 W. Adam and P. A. Ganeshpure Synthesis 1993 281. J. Morey and J. M. Saa Tetrahedron 1993 49 105. W. Li C. Sotiriou-Leventis M. Saha P. P,Fu and R.W. Giese Synth. Commun. 1993 23,97. '* T. Ohno M. Ozaki A. Inagaki T. Hirashima and 1. Nishiguchi TetrahedronLett. 1993 34,2629. 83 I.S.Weitz and M. Rabinovitz J. Chem. SOC., Perkin Trans.1 1993 117. 84 T.G. Grant and A.I. Meyers Tetrahedron Lett. 1993 34,3707. Aromatic Compounds Chiral oxazolines have been prepared from (S)-serine; these chiral auxiliaries show favourable asymmetric induction in a process similar to Scheme Tomioka has employed 2,6-di-t-butyl-4-methoxyphenyIesters (52) as an effective inert electron deficient moiety to facilitate i,6nucleophilic additionto aromatic rings.Incorporation of the chiraf diether (53)in this process affords adducts (54) in high e.e.86 OMe I”! st;”* (54) (53) The reaction mode and selectivity and regoselectivity of the photocycloaddition of 2,3-dirnethylbuta- 1,3-diene (DMBD)and benzene are markedly dependent on the arene substituent.Ingenera1,mixturesofproductsareformed.Thisisinmarkedcontrastto the photoreaction of DMBD and benzonitrile which gives the (4 + 4) photocycloadduct (55) as the major product (Scheme 11).87 Scheme 11 The stereoselectivity of the intramolecular (2 + 2) photocycloaddition to benzenes A.I. Meyers W. Schmidt and M. J. McKennon Synthesis 1993 251. 86 K. Tomioka M.Shindo and K. Koga Tetruhedron Lett. 1993,34,681. ” A. Gilbert and 0.Griffiths J. Chem. Soc. Ferkin Trans. I 1993 1379. A. P.Choriton has been examined.88 A diastereoselective(4 + 2) cycloadditionof singlet oxygen has been observed in the photooxygenation of a chid naphthyl aIcohoi (56) (Scheme 12). These results indicate that the chiral alcohol directs the incoming singIet oxygen.89 R'OYo* R'yoR2 Reagents 0,,TPP hv CDCI, rt Scheme 12 4 Substitution in the Benzene Ring Electrophilic Substitution.-Simple methods to prepare polyiodinated arenes are scarce. Barluenga has developed a method using bis(pyridine)iodonium(I)tetraborate that allows easy access to these iodobenzene derivative^.^' The introduction of iodine into polyalkylbenzenes has also been achieved using N-iodosuccinimide and acidic catalysis?' DiaryIiodonium salts (Ar,I)+X are a very important class of polyvalent iodine compounds.They are generally synthesized indirectly uiaary1 iodides. However by the use of iodofluorosulfate they can be obtained directly from aromatic compounds under mild condition^.^' ips0 substitution of sulfonyl chlorides and of the trimethyl- silyl group with iodine is an excellent regiospecific method for the preparation of aryl iodides.93-95 A number of more selective procedures for introducing bromine into aromatic arnines and phenols have been developed These include the use of hexamethylene tetraamine tribromide pyridinium hydrobromide and N-bromosuccinimide in the presence of primary or secondary arnine~.~~-~~ Bromination of deactivated aromatics has been achieved using bromine trifluoride without the use of a cataIysLg9 A facile conversion of arenediazonium saIts into arylfluorides using boron trifluoride etherate as a solvent has been developed.'00 Arylfluorides can also be obtained regioselectively by the rapid fluorodesilylation of aryltrimethylsilanes using xenon difluoride.lo' '* P.J. Wagner and K. Cheng Tetrahedron Lett. 1993,34,907. 89 W. Adam and M. Prein J. Am. Chem. SOC.,1993 115 3766. '* J. Barluenga J. M.Conzalez M. A. Garcia-Martin and P.J.Campus Tetrahedron Lett. 1993,34,3893. '' P.Bovonsombat and E. McNelis Synthesis 1993,237. 92 N. S.Zefirov T. M. Kasumov A.S. Komin V.D. Sorokin,P. J. Stang and V.V. Zhdankin Synthesis 1993 1209.93 T. Satoh K. Itoh M. Miura and M. Nomura Bull. Chem. Sac Jpn. 1993 66 2121. 91 B. Bennetau and J. Dunogues SYNLETT 1993 171. '' L.A. Jacob 3.-L. Chem and D. Stec Synthesis 1993,611. 96 S. Fujisaka H. Eguch A. Omura A. Okamoto and A. Nishidas Bd. Chem. Soc. Jpn. 1993,66 1576. 97 W. P.Reeves and R. M. King 11 Synth. Commun. 1993 23 855. 98 S.C. Bisarya and R. Rao Syrtth. Conunun. 1993 23 779. 99 S. Rozen and 0.Lerman J. Org. Chem. 1993,58 239. loo K. Shinhama S. Aki T. Farata and 3.-I. Minamikawa Synth. Commun.,1993 23 1577. A.P. Lothian and C.A. Ramsden SYNLETT 1993 753. Aromatic Compounds In the presence of ozone nitrogen dioxide exhibits strong nitrating abilities for alkylbenzenes at low temperature converting them into the corresponding nitro derivatives in high yie1ds.lo2 Use of this nitrating agent on alkyl aryl ketones gives high levels of orthosubstitution along with the meta isomer.This is in contrast to traditional nitrating procedures which lead predominantly to meta sub~titution.'~~ The use of calcium nitrate for the nitration of phenols has been studied. O4 An improved procedure for the nitration of benzocylobutene has been developed usingacetyl nitrate generated in situ by a continuous process in the presence of rnontmorillonite K10 clay."' Work has continued to render the Friedel-Crafts reaction truly catalytic. The Friedelxrafts acylation is generally achieved using a stoichiometric amount of aluminium chloride as a Lewis acid catalyst. This can be problematical on a large scale because the aluminium chloride cannot be reused because of its solubility in the aqueous workup.This problem has been addressed by a number of workers. Friedel-Crafts acylation proceeds smoothly using a catalytic amount of lanthanide triflate which can be recovered and reused.'06 The Friedel-Crafts acyIation can also be carried out in the absence of catalyst using a mixed anhydride. These are prepared by the reaction of a carboxylic acid with trifluoroacetic anhydride in the presence of phosphoric acid or active silicon(1v) catalyst^.^^^^'^^ K10 montmorillonite on its own and impregnated with zinc chloride (clayzic) and other solid acid catalysts have been used for Friedel-Crafts aIkylation~.'~~ These catalysts have a similar activity to aluminium chloride but can be used in smaller quantities and reused.The mild conditions for these catalysts has the added advantage over aluminium chloride that alkyl substituted aromatics can be prepared by the reaction of arenes with allyl alcohol without isomerization ofthe allyl double bond.'" Reduced and reversed reactivity has been observed in the Friedel-Crafts alkylation with clays due to differential adsorption of the reactants onto the solid surface. -I4 The Fries rearrangement of phenyl acetate to ortho-hydroxyacetophenoneis mare selective in the presence of zeolite GaZSM-5." Investigations into the mechanism of the Fries rearrangement in polyphosphoric acid have suggested an intermolecular process.' l6 The amino-Claisen rearrangement can be effected at less severe con- ditions than the thermal process by Lewis acid catalysts.117v11e The synthetic utility of the Friedel-Crafts reaction has been increased by a number of modifications.A gallium dichloride-mediated reductive Friedel-Crafts reaction has been developed Io2 H.Suzuki T. Murashima I. Kogai and T. Mori J. Chem. Suc. Perkin Tram. I 1993 1591. Io3 H. Suzuki T.Murashima A. Tatsurni and I. Kozai Chem. Lett. 1993 1421. Io4 S. C. Bisarya S. K. Joshi and A.G. Holkar,Synth. Commun. 1993 23 1125. lo'P.J. Thomas and R.G.Pews Synth. Comun. 1993 W 505. A. Kawada S. Mitamura and S. Kobayashi J. Chem. Soc. Chem. Commun. 1993 1157. Io7 K. Suzuki,H. Kitagawa and T.Mukaiyama BuU. Chem SOC.Jpn. 1993,66 3729. I*' C. Galli and S. Fornarini J.Chem. SOL Perkin Trans. 2 1993 1147. Io9 0.Sieskind and P. AIbrecht Terrahedroon Lett. 1993,34 1197. *lo P.H. EspecI B. Janssens and P.A. Jacobs J. Org. Chem. 1993,58 7688. *11 G. D. Yadav T. S. Thorat and P. S. Kumbhar Tetrahedron Lett. 1993,34 529. *I2 M. Davister and P. Laszlo Tetrahedron Latt. f993,34,533. *13 S. J. Barlow T.W. Bastock J.H. Clark and S.R. CulIen Tetrahedron Lett. 1993.34 3339. A. Cornelis P.Lado and S. Wang Tetruhedron Lett. 1993,34 3849. 'Is Y. V. Subba Rao S. J. Kulkami M. Subrahmanyam and A. V. Rama Rao Tetrahedron Lett. 1993,34 7799. H. Sbarghi and H. Eshghi Bull. Chem. SOC.Jpn. 1993,66 135. G. Lai and W. K.Anderson Tetruhedron Lett. 1993,34 6849. L.G. Beholz and J. R. StiIIe J. Org. Chem. 1993 58 5095. A.P. Churlton (Scheme 131.' l9 Unconventional regiospecific synthesis of aromatic carboxamides (58) by means of tin-mediated Friedel-Crafts reactions has been achieved (Scheme 13).' *O Thismethodologycan also be used for the preparation ofsulfonamides. Friedel-Crafts acylation and alkylation have been shown to take place in a single stage in the presence of aprotic superacids (Scheme 13).12' -Q R' Reagents i Ga,C1,;'2* ii A1C1,;1210-20"C122 Scheme 13 Conjugated dienones add to electron-rich arenes in a Friedel-Crafts annulation process that creates tricyclic compounds containing a central seven-rnembered ring (Scheme 14).'22 This method has been used as the key step in the synthesis of the diterpene baxbatusol (59).lZ3 A number of interesting Lewis acid mediated electrophihc substitution reactions related to the Friedel-Crafts reaction have been reported (Scheme 15).124-128 Direct aromatic amination has an advantage over the traditional method of reduction of the corresponding nitro compound- A number of novel direct amination methods have been developed.Azides in the presence of trifluoromethane sulfonic acid give the amino diazoniurn cation (RNHN,)' which reacts with arenes to give aromatic amides. 29. 30 Electron-rich arenes are regioselectively aminatedunder mild neutral conditions (Scheme 16).13' 'I9 Y. Hashimoto K. Hirata B.Kagoshima N. Kihara M.Hasegawa and K.Saigo Tetrahedron 1993,49 5969. M.Amswald and W.P. Neumann .I.Org. Chem. 1993,58,7022. 12' I. Akhrem A. OrIinkav and M.Volpin J. Chem. Soc. Chem. Commun. 1993,257. 12' G.Majctich Y. Zhang T. L. Feltman and V. Belfourt Tetrahedron Lett. 1993 34,441. 123 G. Majetich Y. Zhang. T. L. Feltman. and S.Duncan,Jr Tetrahedron Leu. 1993 34,445. J.N. Kim and E. K. Ryu Tetrahedron Lett. 1993,34 3567. 125 A. P.Yakubov D. V. Tsyganov L.I. klenlkii and M. M. Krayushkin Tetrahedron 1993,49 3397. 126 A.R. Katritsky L. Xie A. S. Afridi W.-Q. Fan and W. Kumictkicwicz Synthesis 1993 47. 12' A. W. van der Made and R. H. van der Made J. Org. Chem. 1993 58 1263. ''' G.A. OIah Q. Wang X.-Y.Li and S. Prakash SYNLETT 1993 32. H. Takeuchi T.Adachi H.Nishiguchi K.Itou and K. Koyama J. Chem.Soc. Perkin Trans.I 1993,867. G.A. Olah P. Ramaiah Q. Wang and G.K.S. Prakash J. Org. Chem. 1993 58 6901. 13' I.Zaltsgcndler Y. kblanc and M. A. Bernstein Tetrahedron Lett. 1993 34 2441. 12' Aromatic Compounds Reagents BF,-Et,O (59) Scheme 14 R iii t d VBt R Reagents i EtS 1-CF,CH(O lzt BF,; ii CJ (Cl)(SAr)R BF,; iii (CH,O), HBr IOAc; iv MeOCI AICI,; v ArCN'-O- AICI Scheme 15 P;IH* X = OMe OBn NMe2 Reagents i LICIO,; ii Zn/HOAc Scheme 16 Oxygen can also be introduced directIy into aromatic systems with the use of HOF-CH,CN complex or CH,0F.1.32Tritium can be introduced into activated aromatic compounds using BF,-Et,O and tritiated water. 133 An unorthodox rate enhancement in the Mannich reaction has been observed. M. Kol and S. Rozens J. Org. Chem. 1993 58,1593. P. McGeady and R. Croteau J. Chem.SOC.,Chem. Commun.1993,775. 5,,2an 162 A. P. Chorlton Under classical conditions the Mannich reaction is dramatically slowed after the formation of the mono-substituted product. Leigh has found that introduction of an electron-withdrawing group into the paw-position of phenol facilitates the formation of the disubstituted product in high yields.134 The heating rates associated with microwave heating have been used to control the isomeric ratio in suIfonation of na~htha1ene.l~~ Cerfontain has carried out an in-depth study into the sulfonation of naphthalene containing oxy substituents. 36-13' The thermal decomposition of meta-ditoluidinium sulfate to give ortho-rnethylsulfonic acid has been monitored. The rate-determining step for this reaction appears to be proton transfer to give an absorbed phase of meta-toluidine and sulfuric acid prior to sulfonation.'39 Nucleophilic Substitution.-Aromatic nucleophilic substitution has been the subject of debate by a number of workers. The major issue of interest concerns nucleophilic substitution reactions that occur through a chain process with radicals and radical anions as intermediates. The propagation reactions proposed have been among others the dissociation of the radical anion intermediate of the substrate to give a radical which reacts with the nucleophile (SRNlmechanism) or the reaction of such a radical anion with a nucleophile to give the substitution product (SRN2mechanism). Denney has questioned the validity of the SR,l mechanism because these reactions are known to take place with radical anions that are stable to dissociation thus favouring These claims have been rebuffed by Rossi who favours an S,,1 mechanism based on kinetic gro~nds.'~' Others have also put forward evidence for S,,l mechanisms.142-144 Alternative mechanisms are also possible for aromatic nucleophilic substitution.Zhang has proposed an S,Ztype non-chain radical process in the reaction of p-nitrochlorobenzene with the sodium salt of ethyl ar-cy-an~acetate.'~'**~~ In a study of the hydrolysis of ethers of 2,4-dinitrophenoIs de Rossi has found no evidence for a single-electron transfer mechanism thus pointing to the classical two-electron addition4imination reaction. 14' The mechanism of aromatic nucleophilic substitution where amines are the nucleophiles has been intensively investigated.14' -154 Aromatic nucleophilic substitution with carbon nucleophiles is an important 134 D.A.Leigh P. Linnane and G. Jackson Tetrahedron Lett. 1993,34 5639. 13' D. Stuerga K. Gonon and M. Lallemant Tetrahedron 1993 49 6229. 136 H.R.W. Ansink E. Zelvelder and H. Cerfontain Red. Trao. Chim. Pays-Bas 1993 112 2fO. 137 H. R.W. Ansink E. Zclvelder and H. Cerfontain Red. Trao. Ckim. Puys-Bas 1993 112 216. 13' Ii.R. W. Ansink E. Zelvelder and H. Cerfontain J. Chem. Soc. Perkin Trans. 2 1993 721. G. Singh I.P.S. Kapoor and M. Jain J. Chem. Soc. Perkin Trans. 2 1993 1521. I** B. Denney D.Z. Denney and A. J. Perez Tetrahedron 1993,49 4453. ''* R.A. Rossi and S.M. Palacios Tetrahedron 1993 49,4485.E.C. Ashby R. Gurunmurthy and R.W. Ridlehuber J. Org. Chem. f993 58 5832. S. Montanari C. Paradisi and G. Scorrano J. Org. Chem. 1993 58 5628. I** C. Galli and P. Gentili J. Chem. Soc. Perkin Truns. 2 1993 1135. X.M. Zhang D.-L. Yang and X.Q.-Jia and Y.-C. Liu J. Org-Chem. 1993,58 7350. X.-M. Zhang D.-L. Yang and Y.-C. Liu J. Org. Chem. 1993 58,224. i47 E.B.de Vargas E. L. Setti M. L. Aimar and R.H.de Rossi J. Org. Chem. 1993 58 7354. N. S. Nadelman M. Marder and A. Gurevich J. Chem. SOC.,Perkin Truns. 2 1993 229. *49 R.Chamberlin and M.R. Crampton J. Chem. Res. (S) 1993 106. "O R. Chamberlin and M. R. Crampton J. Chem. Soc. Perkin Truns. 2 1993 75. "' E.T. Akinyele D.-F. Crist and J. Hirst J. Ckem. Soc. Perkin Trans. 2 1993 905. '" S.Sekiguchi M. Hosokawa T.Suzuki and M. Sato J. Chem. SOC. Perkin Trans. 2 1993 1111. lS3 T.A. Emokpae P.U.Uwakwe and J. Hirst J. Chem. Soc. Perkin Trans. 2 1993 125. 15* T. Ibata X. Zou,and T. Demura Tetrahedron Lett. 1993 34,5613. Aromatic Compounds method for the formation of carbon-rbon bonds; a number of examples are given in Scheme 17.'55-160 0 Q / Reagents i H,C=CR(ONa); ii (A); iii ArMgBr; iv (B); v. Na(H,C=CO,Bu') FeSO Scbeme 17 Miyano has demonstrated that Grignard reagents can displace methoxy groups.156*i 57 The scope of this reaction has been extended by the utilization of sodium alkoxides and lithium amides as nucleophiles to give alkoxybenzenes and aromatic amines respective€y.'61.'62 Non-activated aromatic bromides are subject to methoxylation under mild and selective conditions when copper associated with carbon dioxide is used as a catalyst with sodium methoxide.163 2,4-Dinitrochloroben-zene undergoes halogen-exchange fluorination with hydrogen fluoride-base solutions to afford the corresponding fluorides.'64 Aryl phosphines can be readily synthesized from aryl fluorides by nucleophilic substitution with potassium diphenylphosphine. ti5 Regioselective control can be achieved in aromatic nucleophilic substitution of 2?4-difIuorocarbony1 aryls. The carbonyl group of an aldehyde or ketone directs Is' C Dell'Erba M. Novi G. PctriDo and C. Tavani Tetrahedron latt. 1993 34 235. T.Hattori H. Hotta T. Suzuki and S. Miyano Bull. Chem. Soc. Jpn.* 1993,44 613. "'T. Hattori T.Suzuki N.Hayashizaka N. Koike,and S,Miyamo 5uU. Ckem. SOC.Jpn. 1993,6&,3034. W.-Y.Zhao and 2.-T. Huang Syntk Commun. 1993 23,2533. 159 H.Medebielle M. A. Oturan J. Pinson and J.-M. Saveant Tetrahedron LRtt. 1993,34 3409. 16* M. van Leeuwen and A. McKiIlop 3. Chem. SOC.,Perkin Trans. 1 1993,2433. T. Hattori S. Satoh and S. Miyano Bull. Chem. Soc. Jpn. 1993 66 3840. W.ten Hoeve C. G. Krusc J. N. Luteyn J. R. G.Thiecke and €3. Wynkrg J. Org. Chem. 1993,58,5101. 163 D. NobcI J. Chem. Soc. Chem. Commun. 1993,419. 16* T. Fukuhara and N. Yoncda Chem. Lett. 1993 509. S.J. Coote G.J. Dawson C. G. Frost and J. M. J. WiIliams SYNLETT 1993 509. A. P. Chorlton nudeophiIic displacement to the ortho-position in preference to the para-position.s66 The application of vicarious nucleophilic substitution (VNS) of hydrogen allows the direct isocyanornethylation of nitroarenes (Scheme 18).'67 Reagents i Bu'OK DMF; ii CO, AcOEt Scheme 18 A VNS process is thought to be responsible for the facile rnonobromination of 174-benzodithians (Scheme 19).16* Y &-' Br H Br I &I] 9-b;)7a) 1 Br2 HBr Br Br-I Br Br-Scheme 19 An unprecedented intramolecular nucleophilic addition process rather than that of substitution of a diazonium salt has been reported (Scheme 20).169 Reagents i HNO,; ii NifCN) Scheme 20 166 D.M. Fink and J.T. Stupczewski Tetrahedron Len. 1993 34 6525. M. Makosza A. Kimowski and S. Ostrowski Synthesis 1993 1215. R. Caputo M. DeNisco and G. Palumbo Tetrahedron 1993 49 11383.C.A. Panetta Z. Fang and N. E. Heirner J. Org. Chern. 1993 58 6146. Aromafic Compounds 155 A new carboannulation strategy has been developed that involves an intramolecular nucleophilic addition ofsilyl enol ethers to photosensitized electron-transfer generated arene radical cations (Scheme 21).170 Reagents i hv CH,CN H,O; ii 1,4-dicyanonaphthalene Scheme 21 Substitution via Organornetallic Intermediates. The regiospecific nature of directed ortho-metallation (DoM) over cIassica1 electrophilic aromatic substitution methods continues to be exploited in the synthesis of aromatic compounds. Amides and ethers are still the most common DoM groups to be used fur this purpose. The asymmetric synthesis of optically active phthalides via DoM and the efficient conversion of alkylphenols into salicyclic acids are examples of their use (Scheme 22).17 72 0 iii.. Reagents i BuLi; ii RCHO; iii CO,; iv HOAc Scheme 22 A number of other DoM groups have been effectively utilized; these include aromatic aldimines (which act as ortho-lithiated protected aldehydes) and the thiolate group.173.174 The silanoIate group has been evaluated as a DoM group but it suffers from nucleophilic attack thus reducing its synthetic potential.' 75 The regioselectivity of DoM can be effected by manipulation of the side chain adjacent to the amide functionality (Scheme Changing the base used for metallation from an organolithiurn to a superbase also effects the regioselectivity (Scheme 23). 77 170 G.Pandey A. Krishna K. Girija and M. Karthikeyan Tetrahedron Lett. 1993 34 6631. 17' S. Matsui A. Uejirna Y. Suziki and K. Tanaka J. Chem. SOC. Perkin Trans. 1 1993 701. 172 A. R. Katritzky H. Lang and X. Lan Synth. Commun.,1993 23 1175. 173 L. A. Flippin J. M. Muchowski,and D. S. Carter J. Org. Chem. 1993 58 2462. 11A S. Masson J.-F. Saint-Clair and M. Saquat Synthesis 1993 485. S. McN. Sieburth and L. Fensterbank J. Org. Chem. 1993,58 6314. G. Katsoulos and M.Schlosser Tetrahedron Lett. 1993 34 6263. S. Cabiddu C. Fattuoni C. FLoris G. Gelli and S. Melis Tetrahedron,1993 49 4965. A. P. Chorlton OMe Reagents i BuLi; ii E’; iii BuLi BuOK Scheme 23 The efficiencies of DoM for a series consisting of secondary benzamides tertiary bemamines and benzylic alcohols have been reported.It was found for both amidic series that the efficiencies increase as the oxygen and the ortho hydrogen in the substrate are more coplanar with the aromatic ring. However for the alcohol series the opposite order is observed; this is thought to be due to shielding caused by association of the aIkoxide with two lithiurns as opposed to one in the amidic case.17* Palladium-catalysed cross-coupling reactions continue to be widely used for functionalization of aromatic compounds. The utility of the Heck reaction arylation of olefins has been extended to the arylation of vinylamine~”~and to reactions in aqueous media.’ The mode of reaction of the palladium-catalysed reaction of vinyl borate (60)and aryl halides can be varied to favour Heck or Suzuki-type processes by careful control of the reaction conditions (Scheme 24).Ia1 (a) Heck.(b) Suzuki. Reagents ArX Pd(o) scheme 24 The palladium-catalysed coupling between organostannanes and unsaturated P.Beak,S.T. Kerrick and D. J. Gallagher J. Am. Chem. Soc. 1993 115 10268. lt9 C. A. Busacca R.E. Johnson,and J. Swestock .I.Urg. Chem. 1993,58 3299. S. Sengupta and S. Bhattacharga J. Chem. Soc. Perkin Trans. 1 1993 1943. A. R. Hunt S.K.Stewart and A. Whiting. TetrahedronLett. 1993 34,3599. Aromatic Compounds 167 halides or sulfonates the Stille reaction has been the subject of a comprehensive study.182 Aryl alkynes can be synthesized by the palladium-catalysed reaction of aryl triflates with terminal alkynes.183 The synthetic transformations ofaryl triflates has been revie~ed.''~ The biaryl nucleus is present in a number of natural products and is a key feature in chiral catalysts (e.g.BINAP) and in bidentate ligands. This has resulted in new developments in the methodology for their formation. Lipshutz has synthesized biaryls uiu higher order cyano cuprates. (Scheme 25).' 85 Meyers has used oxazohe-mediated biaryl coupling and the Ullman reaction to prepare multifunctional chiral biaryls. 88 The cross-coupling of arytzinc com-pounds with aryl halides has been exploited to prepare unsymmetrical biaryls. 189*190 The mechanism of the Ullman coupling reaction on absorbed monolayers has been studied."' Barrett has developed a catalytic procedure for the oxidative coupling of phenols (Scheme 26).'" &h2+&)ltpFs72 g \ +J$J$ L Me Me (A) Reagents 10mol % (C) Cs,CO, PhBr scheme 26 Organolithium compounds are often formed by bromine-lithium exchange between the appropriate brominated precursors.The use of the more readily available chloroaromatics should be avoided due to their €ower reactivity. This process can be made viable by the addition of a naphthalene ~ata1yst.l~~ The reaction of ortho-V. Farina B.Krishnan D. R.Marshall and G. P. Roth 1.Org. Chem. 1993,58 5434. M. Alarni F. Fern and G. LinstrurneIle Tetrahedron LRtt. 1993 34,6403. K. Ritter SYNLETT 1993,735. B. H. Lipshutz K. Siegmann E.Garcia and F. Kayser J. Am. Chem. Soc. 1993 115,9275. M.Moorlag and A. I. Meyers Tetrahedron Lett.1993,34,6989. H. Moorlag and A.I. Meyers Tetrukdrun Lett. 1993 34 6993. la' T. P.Nelson and A.I. Meyers Tetrahedron Lett. 1993 34 3051. K. Takagi Chem. Lett. 1993,469. S. SibiIle V. Ratovelomanana J.V. NedeIec and J. Perichon SYNLETT 1933,425. 19' M. Xi and 3.F. Bent J. Am. Chem. Sm.,1993 115.7426. 192 A.G.M.Barrett T. Itoh and E. M. Wallace Tetrahedron Latt. 1993 34,2233. 193 A.G. Gudarro D.J. Ramon and M. Yus Tetrahedron Lett. 1993 34,469. 19' 168 A. P. Chorlton haloiodobenzenes with activated copper gives at ambient temperature a stable on ortho-halophenylcoppr reagent. 194 The use of arene chromium tricarbonyl complexes in organic synthesis has been re~iewed.'~',~~~ Substitution via Aryl Radicak The production of aryl radicals from para-methoxyben-zenediazonium tetrafluoroborate is accelerated in the presence of catechol and its derivatives.EPR and spin-trapping investigations indicate that this rednctiun process is catalysed by semiquinone radical^.'^' Aryl radicals are also formed by the reduction of aryltrirnethylammonium cations. Examination of this process demonstrates that the trimethyIammonium group can be expelled in much the same manner as chlorine atoms thus promising application in organic synthesis.fg8 Triphenylsulfonium salts undergo photochemical or electrochemical decomposition to generate aryl radicals. 99 Cyanobenzenes have been shown to undergo photochemical substitution with olefins allylic organornetallics and alkyl silanes (Scheme 27).200-202 CUZR I $R + CN I 6+ CN YR1 =LR3-NC NC Reagents i hv CH,CN; ii hv RSiMe,Y Scheme 27 A number of new photochemical methods have been developed that allow the introductionof fluorinated alkyls into the aryl nucleus.Mallouk has demonstrated that silver triflate can be used as a source of trifluoromethyl radicals which subsequently 194 G. W. Ebert D. R. Pfenning S. D. Suchen and T.A. Donovan Jr. Tetrahedron Lett. 1993 34,2279. 19' S.G. Davies and T.J. Donohoe SYNLETT 1993 323. 19' M. Sodeoka and M. Shibasaki SYNLETT 1993 643. 197 K. J. Reszka and C.F. Chignell 1.Am. Chem. SOC. 1993 115 7752. 19' V. V. Konovalov I. I. Bilkis B. A. Selivanov V. D. Shteingarts,and V. D. Tsvetkov J. Chem.Soc. Perkin Trans. 2 1993 1707.199 A. Stasko P.Rapta V. Brezova 0.Nuyken and R. Vogel Tetrahedron i993 49 10917. K. McMahon and D. R. Arnold Can. J. Cbem. 1992 71,450. '** K. Nakanshi K. Mizuno and V. Otsuji Bull. Chem. SOC.Jpn. f993,66 2371. 202 M. MelIa N. d'Alessandro M. Freccero and A. Albini J. Chem. Soc. Perkin Trans. 2 1993 515. Aromatic Compounds can substitute C-h~drogen.~'~ Perfluoroalkylation of anilines has been reported; this process involves initial charge-transfer complex formation between the aniIine and perfluoroalkyl iodides. The complex then undergoes photo-induced electron transfer to give a radical cation intermediate which attacks the ar~iline."~ Penta- fluorophenylation of arenes can be effected via photochemical-induced reaction of pentafluorophenylalkane sulfonates with a wide variety of aromatic compounds.205 Di- and trihalobenzenes undergo ips0 substitution on reaction with benzyl radicals to give halo- and dihalodiphenylmethanes respectively.206 Intramolecular radical ips0 substitution is thought to be responsible for the conversion ofarylpropyl bromides (611 into arylpropanols (62)(Scheme 28).207 (611 Reagents [CH,(CH ,SnH Scheme 28 The oxidation of benzene to phenol with Underfriend's reagent (Fe2+-EDTA + 0 + L-absorbic acid) has been examined and evidence is presented fur hydroxyl radicals as the activated species.203 5 Condensed Polycyclic Aromatic Compounds Benzenoid Aromatics.-The discovery that buckminsterfullerene CeO,is a stable molecule due to geodesic and electronic properties has generated a renewed interest in hydrocarbons that resemble a portion of the C, surface.The carbon framework of corannulene (53)can be considered to represent the poIar cap of C60.In spite of its curvature corannulene undergoes rapid bowl-to-bowl inversion. Incorporation of the corannulene structure into C6,, would require the bowl to be in a locked conformation. Rabideau has demonstrated that the bowl becomes rigid with only the addition of two carbons thus giving the fused five membered ring derivative The corannuhe tetraanion has also been subject of debate. The possibility of the. tetraanion being viewed as a cyclopentadienyl anion inner core with the remaining three electrons at the periphery of the molecule producing an 18-x-electron trianion has been raised.Calculationsdo not lend much support to this hypothesis and attempted formation of lo the tetraanion and protonation have also The bowl shaped hydrocarbon sumanene (55)can also be regarded as a precursor to the synthesis of C60. The synthesis of sumanene has not been reported; Mehta has reported his achievements towards this target but unfortunateIy this route fails at the '03 C. Lai and T. E. Malbuk J. Chem. SOC.,Chem. Commun. 1993 1359. Q.-Y. Chem Z.-T. Li and C.-M. Zhou J. Chem. Soc. Perkin Trans. 1 1993 2457. '05 Q.-Y. Chen and Z.T. Li J. Org. Chem. 1993 58 2599. '06 R. Henriquez and D.C. Nonhebel Tetrahedron I993,49,5497. '07 E. Lee C. Lee J.S. Tae H.S. Whang and K. S. Li Tetrnhedron Lett. 1993 34 2343. '08 S. Ito K.Ueno A. Mitarai and K. Sasaki J. Chem. SOC., Perkin Trans. 2 1993 255. '09 A. H. Abdourazak A. Sygula and P. W. Rabideau J. Am. Chern. SOC. 1993 115 3010. 'lo P.W. Rabideau Z. Marcinow R. Sygyula and A. Sygyla Tetrahedron Lett. 1993 34 5351. 170 A. P. Chorlton Reagents FVP 850 "C lo-* Torr Scheme 29 last step" (Scheme 29). Plater has suggested the synthesis of C, from suitable polycyclic aromatic hydrocarbon (PAH) precursors. A number of appropriate PAHs have been syn-thesized towards this aim the most complex king 1,3,5-tri(benzol[c]phenanthren-9-y1)benzene (66),which could be envisaged under suitable gas-phase dehydrogenation conditions to close up like the petals of a Bower to yield C,,.2'* (66) Cydopentene-fused PAHs are related to C, in that they are constructed of fused hexagonai and pentagonal arrays of carbon atoms.The reactivity of these nonalternate 'I' G. Mehta S. R. Shtah and K. Ravikurnar J. Chem. Soc. Chem. Commun. 1993,1007. M.J. Plater SYNLETT. 1993 405. Aromatic Compounds PAHs is frequently different from alternate PAHs. A detailed study of the electronic behaviour of a series of nonalternate PAHs has been accompIished using heavy atom perturbation effects.213 Methylene bridged PAHs are ubiquitous environmental pollutants often formed by incomplete combustion of fossil fuels. These PAHs have been shown to exhibit potent tumourigenic activity. However surprisingly little is known concerning their chemistry or biological properties. This situation has been remedied by the synthesis of these compounds by standard te~hniques.~’~-~l~ The electrophilic substitution and the catalytic reduction of a number of these PAHs has been studied.218-220 Th e carcinogenic properties of PAHs are thought to be due to oxidation of the bay region to give diol epoxides (67) which are implied as the ultimate carcinogenic metabolites.Evidence for this is the identification of its metabolic precursor trans-3,4-dihydrodiol (68). To permit biological study of these systems a number of workers have disclosed synthetic routes to these -224 Flash vacuum pyrolysis has proved to be useful in the synthesis of acenaphthylene and its derivatives (Scheme 30).225-227 The simple and rapid production of complex PAHs has been demonstrated; a number of the more interesting examples are highlighted in Scheme 31.2281230 Non-benzenoid Aromatics-l,6-Methano[ lO]annulene (69) a l0x-electron system can also exist in the less stable bisnorcaradiene form (70).Neidlein has demonstrated that bridging between the C-2and C-10 positions shifts the equilibrium in favour of the bisnorcaradiene structure (71).231 ’I3 B. F. Plummcr L. K.Steffen,T.L. Braley W. G. Recse K.Zych G.Van Dyke,and B. Tully J. Am.Chem. Soc. 1993 115 11542. 214 C. Yang and R.G.Harvey 3. Org. Chem. 1993.58,4155. 215 P. P. J. MuIdcr B. B. &re J. Comelisse and Lugtenburg Red. Trau. Chim. Pays-Bas 1993 112,255. 216 T. Gimisis J. W. Kampt and M. Koreeda J. Org. Chem. 1993,sS 5858. 217 M.J. Tanya and J. E. Bupp J. Org. Chem.1993,58,4173. B. P.Cho M. Kim,and R.G.Harvey J. Org. Chem. 19!43,58 5788. 219 M.Minabe R.Nishimura T. Kimura and M. Tsubota BuU. Chem. SOC.Jpn. 1993 66 1248. ”* M.Minabe S. Urushibara F. Mishina T. Kimura and M. Tsubota Bull. Chem.Soc. Jpn. 1993,66,670. ’” P. K.Sharma Synth. Cummun. 1993 23 389. 222 R.J. Young,C. Cortez E. Luna H. Lee and R.G.Harvey J. Org. Chem. 1993 58 356. 223 R. Agarwal and D. R. Boyde 3. Chem. Soc. Perkin Trans. 1 1993 2869. 224 Y.4. Wu J.-S.hi and P.P. Fu J. Org. Chem. 1993 58 7283. ’’’ R. F.C.Brown F. W. Eastwood and N. R. Wong Tetrahedron Lett. 1993 34 1223. 226 R.F.C. Brown,F. W. Eastwood and N. R. Wong Tetrahedron Lett. 1993 34 3607. U. E. Wiersum and L. W. Jeneskens Tetrahedron Lett. 1993 34 6615. G. Dyker J. Korning P.G.Jones and P.Bubenitschek Angew. Chem. Int. Ed. En& 1993,32 1733. 229 F.M. Raymo M. F. Pans and F. H. Kobnke Tetruhedron Lett. 1993 34 5331. 130 A. Ghanirni and J. Sirnonet Tetrahedron Lett. 1993 34 6893. 231 R. Neidlein and U. Kux Angew. Chem. Int. Ed. Engl. 1993,32 1324. A. P. Chorlton Scheme 30 Azulenes with systems that have a peripheral 14z-electron (72) and an 18n-eIectron (73)conjugation have been synthesi~ed.~~~.~~~ These systems show little contribution from the extra conjugation but rather are composed of two separate azulene-type n systems as in (73) and azuIene and fulvene systems as in (72). A series of methano-bridged-tetrahydro[2U-j- -[24]- -[25]- -[28]- -[30]- and -[32]annulenediones (74a)-(74f) have been synthesized.These compounds were expected to show the ring-current effect for the [4n + 21. or [4n]n-electron system arising from polarization of the two carbonyl groups. However contrary to these expectations the annulenediones showed weak tropicity presumably due to a low planarity of their molecular skeleton. The dication from the tetrahydrornethano[24]- annulendione (74b) is strongly diatropic due to possession of a 22n-electron aromatic system.234A similar dication of the methano[24]annulenedione (75) exhibits the strongest diatropicity recorded for a 22~-electron system.235 In an analogous study methanohomoC1 Slannulene (76) and methanohomo[ Wlannulene (77) were prepared. Protonation of these species should yieId the corresponding 1471 and Mz-electron 232 M.Yasunami J. Hoioki Y. Kitamori I. Kikuchs and K.Takase Bull. Chem. SOC.Jpn. 1993,66,2273. 233 M. Nitta K. Nishimura and Y. Ino Tetrahedron Lett. 1993 34 2157. 234 H. Higuchi K. Asano K. Nakafuku Y.Takai J. Ojima,andG. Yamamota,J. Chem.Suc. Perkin Trans. I 1993 89. ”’ G.Yamamoto H. Hignchi K. Asano and 1. Ojima Chem. Lett. 1993 1829. Aromatic Compounds jI OR OR OR OR Reagents:i 1,%-diiodonaphthalene;ii 1-iodonaphthaIene;iii mthracene xylene; iv HCIO, EtOH; v -&- -6H' Scheme 31 174 A. P. Chorlton OD OD (74a) [m]; m = n = 0 (74b)[24]; m = n = 1 (74c) pq m = 1; n = 2 (744 [28]; m = n = 2 (748) (3UJ; m = 2; n = 3 (740 1321;TI = n = 3 systems respectively. Attempts at the protonation of (76) and (77)were unsuccess- fu1.236 Hay coupling of the tetraethynylethene (78) gives the t12lannulene (79) and the [18]annulene (80); spectral examination of (79) and (80) confirms the expected antiaromatic character of the 12x-electron system and the aromatic character of the 18 n-electron It has been demonstrated that resonance stabilization in [25]annulene (81) is nut sufficient to stabilize the molecule in a planar conformation with aromatic properties.However if this 26~-electron perimeter incorporates four pyrrole units as in the L261porphyrin (82) then sufficient stabilization is present and the expected aromatic character is exhibited.' 38 6 Cyclophanes The strain and distortion imposed upon the benzene ring in cydophanes imparts an 236 H.Higuchi T. Hashimoto K. Nakafuku,J. Ojima and G.Yamamoto Bull. Chem.Soc. Jpn. 1993,66,294. 237 J. Anthony C. 3. Knobler and F. Diederich Angew. Chem. Znt. Ed. Engl. 1993,32,406. "* T. Wessel B. Franck M.Moller U. Rodewald and M. Lage,Angew. Chem. Int. Ed. Engl. 1993,32,1148. Aromatic Compounds R' x* R3 (78) Ff CuCl TMEDA I R RlR R + enhanced reactivity which can subsequently lead to unusual reactions. [6]Paracyc- lophanes undergo nucleophilic addition with Bu"Liand Bu'Li and formal nucleophilic substitution with Bu'Li. This is an example of nucleophilic substitution being effected under mild conditions considering that the benzene ring is not activated by strongly electron-withdrawing groups. This result is ascribed to the release in strain on the formation of the initial adduct (Scheme ?2).''' C2.2)Metacyclophanes undergo a novel Lewis-acid catatysed transannular cycliz- ation.The cyclization is attributable to the different Ir-electron densities of the two benzene rings which are separated from each other by two ethylene units (Scheme 33).240 Similar transannular cycIizations have been observed in the bromination of &substituted [2)metacyclo[2]( 1,3)pyrenophane~.~~' Transannular interactions in [2.2Jmetacyclophanes aIso affect the selectivity of the tricyanovinylation reaction with 239 Y.Tobe M.limbo S. Saiki K. Kakiuchi and K. Naemura J. Org. Chem. 1993.58 5883. 240 T. Yamato J.4. Matsumoto M. Shigekuni T. Ishili and M. Tashiro J. Chem. Res.(S) 1993,272.241 T. Yamato A. Miyazawa and M.Tashiro 1.Chem. Soc. Perkin Tram. I 1993 3127. A. P. Chorlton Reagents i RLi Scheme 32 Scheme 33 tetracyanoethylene (TCNE). In addition to the normal N-tricyanovinyl product 4-arnino[2.2]metacyclophane reacts with TCNE to give oxaziridine derivatives (Scheme 34).242 Scheme 34 The highly strained Adamantanophane (83)renders the benzene ring susceptible to dienophile addition in a Diels-Alder reaction.243 Similar Diels-Alder reactions with the mono-(Dewar benzene) isomer of [l .l]metacyclophane have also been observed (Scheme 35).244 The intramolecular interaction between the aromatic rings of small cyclophanes has been the subject of a number of investigations. 8,16-Dimethoxy[2.2]metacyclophane (84) undergoes the diazo coupling reaction easily in one ring but never in both.The absorption maxima of a series of azo compounds was found to be bathochromically shifted from those of model reference compounds. When the A,, values of the azo compound that carries a functional group in the couter (C-13) position are plotted 14' A.A. Aly A. A. Hassan and A.-F.E. Mourad Can. .I.Chem. 1993,71 1845. 2A3 R. Lernmen M. Nieger and F.Vogtle J. Chem. SOL Chem. Comun. 1993,1158. "* G.W. Wijsman D. S. Van Es W. B.de Wolf and F. Bickelhaupt Angew. Chem. Inr. Ed. Engl. 1993,32 726. Aromatic Compounds Reagents MeO,CCECCO,Me; ii 0 Scheme 35 against the substituent Hammett constants (a,p) a straight line is obtained. These results establish that the electronic effects of the functionaI group are transmitted between the two aromatic rings in [2.2]metacyclophanes by a through-space interaction (Scheme 36).245 (W Reagents PhNl Scheme 36 Through-space interactions have also been observed in the stabilization of the naphthyl- 1-tropylium ion by [2.2]paracycIophane fixed at the position (C-8-C-5') face-to-face to the tropylium ring (85).246 The electronic properties of benzoannelated C22lparacyclophane (86) have been studied; such rnoIecuIes are found to be highly efficientelectron acceptors.The unusual geometry of the carbon framework alIows reversibk acceptance of four to six electrons thus making it an attractive model for a charge-storage system.247 The last and most 245 A. Tsuge,T. Moriguchi S.Mataka and M.Tachiro J. Chem. Soc. Perkin Trans. I 1993,2211. ''' K. Kornatsu R. Tsuji Y. Inouc and K. Takeuchi Tetrahedron Lett. 1993,34,99. '" 0.Reiser B. Konig K. Meerholz J. Heinze T. Wtllauer F. Gerson R.Frim M. Ravinovitz and A. de Meijere J. Am. Chern. Soc. 1993 115 3511. A. P. Chorlton strained [2.2]cyclophane (87) has been synthesized; the thermal isomerization of the Dewar benzene valence isomer (88) is the key step.248 248 Y.Tobe M.Kawaguchi K.KakiuLhi and K.Naemura J. Am. Chem. Soc.,1993,115 1173.

ISSN:0069-3030    

DOI:10.1039/OC9939000145

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

7 Heterocyclic Compounds By P.W. SHELDRAKE SmithKline Beecham Pharmaceuticals Old Powder Mills nr Leigh Tonbridge Kent TN11 9AN UK 1 Threemembered Rings Oxiranes are valuable intermediates standing at the interface of acyclic and heterocy- clic chemistry and provide interest to both areas. Oxiranes exempIified by (11 can be prepared stereoselectively and rearrange on treatment with stannic chloride to give keto-alcohols (Z),again stereoselectively and in excellent yield (Scheme 1).’ Reagents i SnCl Scheme 1 Lithium tetrachlorocuprate(r~) has been shown to be efficient at opening epoxides to give chloro-a1cohok2 For example the bis-oxirane (3)gives (4) in 65% yield (Scheme 2). Reagents i Li2CuCl, THF Scheme 2 When the racernic oxirane (5) is treated with acid the product is a (racemic) C.M.Marson A. J. Walker J. fickering A.D. Hobson R. Wrigglesworth and S. J. Edge J. Org. Chem. 1993,58,5994. 2.-X. Guo,A. H. Haines and R. J. K. Taylor SYNLETT. 1993 607. P. W.Sheldrake tetrahydrofuran (6). However on treatment with antibodies raised against (7) the product is predictably optically active but is the tetrahydropyran (8) (Scheme 3).3 f" -0.g Me02 (7) Reagents i H+; ii antibodies Scheme 3 The biosynthetically-patternedcascade oxirane cyclization of (9)has been used as a key step to produce (lo),in 30% yield in studies directed towards the synthesis of etheromycin (Scheme 4).4 Reagents i 0.5 M HCL THF Scheme 4 Treatment of hydroxylamine derivatives (1 1)with sodium hydride in the presence of suitable olefins (12) gives aziridines (13) in yields of up to 95% (Scheme 5).5 K.D.Jandu C.G+Shevlin and R.A. Lerner,Science 1993,259,490. 'I. Paterson R.D. TilIyer and J. B.SmaiI1 Tetrahedron Lett. 1993,34,7137. M. M.Pereira P. P. 0.Santos L. V. Reis A.M. Lobo and S. Prabhaker J. Chem. Soc. Chem. Commun. 1993 38. Heterocyclic Compounds Reduction of 6H-1,2-oxazines (14) with lithium aluminium hydride gives aziridincs (lS).' The cis-isomer predominates; for example where R' = R2= Me the yield is 64% with a 94 :6 ratio of cis :trim (Scheme 6). 0 Ar Reagents i NaH Scheme 5 Reagents i LiAIH, Et,O Scbeme 6 The chiral auxiliary (16) has been used in the asymmetric synthesis of aziridines (18) fromoIefins (17).7 Enantiorneric excesses up to 96% were observed with yields up to 76% (Scheme 7).Reagents i PhFNTs CuOTf (16) Scheme 7 Dimethyldioxirane has been used to oxidize furans (including furan itself) to maleaIdehydes.* These were reacted in situ e-g. with Wittig reagents and the products isolated in good yields (Scheme 8). MethyI(trifluoromethy1)dioxiraneoxidizes unactivated carbon-hydrogen bonds in R.Zimmer. K.Hommann and H.-U. Reissig Liebigs Ann. Chem. 1993 1155. ' D. A. Evans M.M. Fad,M.T. Bilodcau B. A. Anderson and D. M. Barnes J. Am. Chem. Soc. 1993,115 5328. a B.J. Adger C. Barrett J. Brennan P. McGuigan M. A. McKervcy and B. Tarbit J. Chem. Soc. Chem. Commun. 1993,1220. P.W. Sheldrake amine salts with remarkable ~electivity.~ The ultimate products from derivatives of pentylarnine salts (19) are 3,4,5,6-tetrahydropyridines(20) (Scheme 9).I rn I1 OXwC02El CHO CHO 04% * Reagents i dimethyldioxirane;ii Ph,P=CHCO,Et (1 equiv.) &heme 8 Reagents i methyl(trifluoramethy1)dioxirane Scheme 9 The oxaziridines (21) transfer the N-Boc group to nitrogen or carbon nucIeophiles.** (21) X= H,CN 2 Four-membered Rings There are reviews of industrial transformations of penicillins and cephaiosporins' and of 0x0 and imino-functionalized 1,2-0xazetidines. On treatment with silver triflate the silyl enol ethers (22) cyclize onto the oxonium ion intermediate and an oxetane is annulated to the existing ring giving the unusual bicycles (23) (Scheme Reagents i AgOTf CH,CI, 4A Sieves Scheme 10 Tin bis(hexamethyldisi1azide) was studied as a reagent for converting esters into G.Asensio M.E. Gonzalez-Nunez C. B.Bernardini R. MeIlo,and W. Adam,J. Am. Chem.SOC.,1993,115 7250. lo J. Vidal L. Guy S.Stenn and A. Collett J. Org. Chem. 1993,58,4791. J. Verweij and E. de Vroom Red. Tmo. Chim. Pays-Bas,1993 112,66. D.Monderhack J. Heterocycl. Chem. 1993,30 579. l3 D. Craig and V. R.N. Munasinghe J. Chem. Soc. Chem. Commun. 1993,901. Heterocyclic Compounds secondary amides14 and was found to be efficient in cycIizing #?-alkylamino esters to /3-lactams (Scheme ll)." Reagents i. Sn[N(SiMe,),] scheme 11 Ally1 diethyl phosphate was used to form an ally1 palladium species from which b-lactams(24) were constr~cted'~ by carbonylation followed by reaction with an imine (Scheme 12).The 2-aza-1,3-dienes (25) were prepared in good yield. I' Staudinger reaction with acid chlorides gave fi-lactams (26) in which the cis isomer predominated and from which the nitrogen substituent was removed using potassium permangarsate (Scheme 13). Reagents i CO; ii truns-R'CH=NR2 scheme 12 (25) Reagents i RCH,CQCl Et,N; ii KMnO Scbeme 13 A new synthesis of the important intermediate (29)was reported" starting with the furanyl /?-lactarn (28). Degradation of the furan was brought about using singlet oxygen and the resuIting proxy-cumpounds rearranged thermally (Scheme 14). A radical-mediated ring closure formed the carbapenam (31)from the dithiane (30) (Scheme 15)." Another radical-mediated cyclization2" demonstrated formation ofthe f4 W.B. Wang J. A. Restituyo and E.J. Roskamp Tetrahedron Lett. 1993,34,7217. I' W.-8. Wang and E.J. Roskarnp J. Am. Chem. Soc. 1993 115,9417. I6 S. Toni. H. Okumoto M. Sadakane A.K.M. A. Hai and H. Tanaka Tetrahedron Lett. f993,M 6553. G. I. Georg P. He J. Kant and Z.J. Wu J. Org. Chem. 1993,58 5771. '' J. E. Lynch W. L. Laswell R. P. Volante R. A. Reamer D. M.Tschaen,and I. Shinkai Heterocycles 1993 35 1029. l9 J. Anaya D. €I. R. Barton S. D. Gero M. Grande N. Martin and C. Tachdijian Angew. Chem. Int. Ed. Engf, 1993,32 867. '* H. Ishibashi C,Karneoka A. Yoshikawa R. Ueda K.Kodama,T. Sato and M. Ikeda SYNLETT. 1993 649. 184 P. W.Sheldrake B-lactam ring itself in the conversion of (32) into (33) (Scheme 16).TBDMSO g3Q TBDMSO TBDMSO 9 0 Reagents i lo2; ii KOAc Scberne 14 Reagents i 3u,SnH AfBN Scheme 15 i ____) SPh 50% FMB Reagents i BuJnH AIBN Scheme 16 Titanium tetrachloride was used to cyclize (34) to the carbapenem (35) (Scheme 17),2*which was taken on to thienarnycin. Irradiation of a powdered inclusion complex of N-(aroyImethy1)lactams (36)in the chiral auxiliary (37) produces the azetidino-lactams (38) in yields up to 59% and up to 98% enantiomeric excess (Scheme 18).” G. B. Feigelson Tetrahedron Lett. I993,34,4747. ’’F. Toda K.Tanaka 0.Kakindii and T. Kawakami J. Org. Chem. 1993,58 3783. 185 Heterocyclic Compounds OH CO~PNB (34) (35) Reagents i TiCI, CH,CI Scheme 17 Ar H Ho-9 0 Ph2C-OH (36) (37) Reagents i (37); ii hv Scheme 18 Rhodium(1r) acetate mediated closure of the diazo-esters (39) has been studied (Scheme 19).23When n = 0 there is no ring closure because the sulfur interferes with the carbene intermediate; for the sulfoxide or sulfune the reaction is fairly efficient.The chemistry of the 3-methylidene-#Hactams (41) has been in~estigated:~~ the double bond can be epoxidized or cyclopropanated and is a good MichaeI acceptor arid dienophile. On reaction with a hydrazine (Scheme 20) the primary product is the spiro compound (42) from which it is possible to obtain the pyrazole (43). (39)n = 0.1,2 (4) Reagents i Rh,(OAc) Scheme 19 Deprotection ofb-lactam (44)with ceric ammonium nitrate proceeds as e~pected.~ However on similarIy treating its diastereoisomer (45) there is an unprecedented oxidative ring transformation giving (46) in high yield (Scheme 21).'' P. Bissolino M. Alpegiani D. Botghi E. Perrone and G. Francexhi Heterocycles 1993,36 1529. '' S. Gurthler M. Johner S. Ruf and H.-H. Otto Helv. Chim. Acba 1993 76 2959. 25 F. Bertha J. Fetter M. Kajtar-Peredy G.M. Kesura K. Lernpot L. Parkanji,and J. Tarnas Tetrahedron. 1993,49 7803. P. W.Sheldrake The b-lactams (47a) and (47b)on treatment with stannous chloride give rise to a pyrazine dione (48a) or 1,4-oxazine dione (48b) (Scheme 22).26 Reagents i RNHNH Scheme 20 The #?-lactam (49) is readily opened with dimethyloxosulfunium methylide and the product cyclizes on treatment with rhodiurn(I1) acetate to give the 3-ketopyrrolidine (50) (Scheme 23).27 The silacyclobutane (51 reacts with lithium carbenoids thus undergoing ring expansion to give 2-iodo-1,l-dimethyl- 1-silacyclopentane (52) (Scheme 24)'' ""a OMe t 64% I909C x..y2 0 Reagents i (NH,)Ce(NO,) scheme 21 26 B.AIcaide Y. Martin-Cantelejo 3. Rodnquez-Lopez and M. A. Sierra J. Org. Chem. 1993,58,4767. " J. E. Baldwin R. M. AdIington C. R.A. Godfrey D.W,Gollins and J.G. Vaughan 1.Ckm.Soc. Chem. Commun. 1993 1434. K. Matsumoto Y. Aoki K. Oshima K. Utirnoto and N. A. Rahman Termhedron 1993,49 8487. Heterocyclic Compounds (474 X=NAr (47b) x=o (4&) X=NAr(a)x=o Reagents i SnCl -2H,O Scheme 22 tw Reagents i Me,SOCH, DMSO; ii Rh fOAcf Scheme 23 Bis(diisopropy1amino)phosphanylazide (53) reacts with dimethyl acetylenedicar- boxylate to give the six-membered ring (54),29 from which on heating nitrogen is lost producing the I,2-i5-azaphosphate (55) (Scheme 25).The product is air-stable and melts (mp 109-1 10"C)without decomposition! Reagents i LiCHI Scheme 24 3 Five-membered Rings A review of the use of isocyanides in heterocyclic synthesis" predominantly covers five-membered rings. More specifically there are reviews of new chemistry of oxa~oles,~ and recent progress in preparation and synthetic uses of 3H-pyra~oles,~~ the preparation and reactions of indolin-2(3H)-ones ox in dole^).^^ J. Tejeda R. Reau F. Dahan and G.Bertrand 1.Am. Chem. Soc. 1993 115 7880. 30 S.Marcaccini and T.Torroba Org. Prep. Proced. Int. 1993 25 143. 31 A. Hassner and B. Fischer Heterocycles 1993,35 1441. 32 T.Nagai and M. Hamaguchi Org. Prep. Proced. lnt. 1993 25,403. '' G.M. Karp Org. Prep. Proced. int. 1993,25,483. P. W. Sheldrake +-(P~:N)~P-N=N=N Reagents i MeO,CCECCO,Me; ii A Scheme 25 There is a review of the lateral metallation of i~oxazoles.~~ Metallation of heterocycles continues to grow as a powerful synthetic tool complementary to 'classical' synthetic routes. A definitive pape? on the metallation of benzo-fused nitrogen heterocycles covers reaction both adjacent to nitrogen with formamidine derivatives (56) and in the aromatic ring with t-butoxycarbonyl derivatives (58) (Scheme 26).The t-butoxycarbonyl derivatives of pyrrolidine piperidine and hexamethyleneimine can also be lithiated efficiently (Scheme 27).36 Dilithiation of #l-bromo-/?-trimethylsilylstyrene37 (60)gives an intermediate (61)into which can be inserted as the heteroatom sulfur selenium tellurium phosphorus arsenic antimony bismuth silicon germanium or tin (Scheme 28). Both enantiomers of imidazoline (63) are available via resofution. Lith-iation-alkylation gives (64)from which amino acids are obtained in high yield and high optical purity (Scheme 29).38 l-Substituted-l,2,4-triazoles, where the substituent is an alkyl or diethoxymethyl group have been lithiated at the 5-position and reacted with a range of ele~trophiles.~~ 1-Substituted-4-iodoimidazoles treated with ethyl magnesium bromide followed by an electrophile react at the 4-p~sition.~' Nu products from isomerization of the 4-metallated imidazole to the 2-metalIated species were detected.The intermediates (66) and (57) have both been funned41by direct deprotonation of the corresponding acids. 34 N. R. Natale and Y. R. Mirzaei Org. Prep. Proced. Int. 1993,25 517. 35 A.I. Meyers and G. Milot J. Org. Chem. 1993,58,6538. 36 P. Beak and W. K. Lee J. Org. Chem. 1993 58 1109. 37 J. Kurita M. Ishii S. Yasuika and T. Tsuchiya J. Chem. SOC. Chem. Cornmun. 1993 1309. 38 S. Blank and D. Seebach Angew. Chem. Int. Ed. Engl. 1993 32,1765. '' S. Ohta I. Kaawasaki A. Fukuno M. Yamashita,T.Tada and T.Kawabata,Chem. Pharm. Bull. 1993,41 1226.40 R.M.Turner S.V. Ley and S. D. Lindell SYNLETT. 1993,748. 4J C.D. Buttery R.G. Jones and D.W. Knight J. Chem. Soc. Perkin Trans. I 1993 1425. Heterocyclic Compounds (56) n = 1,2.3 (57) I ii E C0,Bu' (58) n = 1,2.3 Reagents i Bu'Li; ii electrophile E Scheme 26 QI Boc Reagents i RLi TMEDA; ii electrophile E Scheme 27 r 1 Reagents i Bu"Li Et,O; ii for M = S (PhSo,),S; for M = Se Se;for M = AsPh PhAsC1,; for M = SiMe, Me,SiCI Scheme 2.8 Reagents i LDA THF -78 T;ii RX; iii CF,CO,W CH,CI,; iv W,Of Scheme 29 P. W.Sheldrake The mesylate and tosylate (68) undergo intramolecular cyclization involving the oxygen of the ether linkage to give the tetrahydrofuran (69)?2The reaction occurs in warm DMF or in acetone or acetonitrile provided the last two solvents contain lithium bromide (Scheme 30).Reagents i Me,C=O LiBr or MeCN LiBr Scheme 30 On treatment with AIBN/tributyltin hydride the bromide (7Ua) forms a radical which ring closes to give the tetrahydrofuran (71a).43 A tetrahydropyran (71b) is available by the same methodology (Scheme 31). 4-Substituted furan-2-ylacetic acid esters are available by the route shown in Scheme (7oa)n = 1 f7ob) n=2 (71a) n =1 (71b) n =2 Reagents i Bu,SnH AIBN Scheme 31 Di- ti- or tetrasubstituted furans are available45 by base-catalysed cyclization of hydroxyenynes (72); some variations and simplification^^^ of the idea are shown in Scheme 33. 42 W. Verbroom,Y. Momherin E. Kelderman J.F. J. Engbersen,G.I. van Humrnel S. Harkema and D.N. Reinhoudt Red. Trav. Chirn. Pays-Bas 1993,112 549. 43 E. Lee J. S. Tae C. Lee and C.M. Park Tetrahedron Lett. 1993 34,4831. 44 R.W.Carling and P.D. Leeson SYNLETT. 1993,40. " 1-A Marshall and W.J. DuBay 3.Org. Chem. 1993 58 3435. 46 J. A. Marshall and W.J. DuBay 1.Org. Chem. 1993 58 3602. Heterocyclic Compounds Reagents i (Et02CCH,),C=O; ii KOH; iii CH,COCl; iv EtOH; v Cu,O quinoiine Scheme 32 HO (74) (75) R (76) Reagents i KOBu' Bu'OH 18-crown-6;ii NaOMe scheme 33 Benzotriazole is a versatile reagent. Just one of its new uses involves setting up the intermediate (78) which by cyclization and elimination of benzotriazole gives benzofurans (79) (Scheme 34).47 The sugar-derived triflate (80)is converted into (81) in high yield by but in base the more unusual bicycle (82) is produced with almost equal efficiency (Scheme 35).The unsaturated ketal (83) gives diol (84) in high yield and enantiomeric excess by Sharpless asymmetric dihydro~ylation.~~ Treatment with acid completes an efficient synthesis of (+)-em-brevicomin (Scheme 36). 47 A. R. KatritzLy X. Lan and Z. Zhang J. Heterocycl. Chem. 1993 381. J. R.Wheatley C.J. F. Bichard S. J. Mantell J.C. Son,D.J. Hughes G. W. J. Fleet and D. Brown,J. Chem. SOC.,Chem. Comn. 1993 1065. 49 J. A. Sodequist and A.M.Rane Tetrahedron Lett. 1993 34,5031. P. W. Sheldrake Reagents i TsOH AcOH Scheme 34 OH n i.H A hr OH Reagents i 9BBN; ii EtCH=CHBr Pd(PPh3), NaOH; iii OsO,,DHQD-PHAL; iv TsOH Scheme 36 The tertiary alcohoi (85) when treated with potassium hydride provides the only example of an anionic oxy-Cope reaction on a simple furan by rearranging to (86) in good yield (Scheme 37)'' Iodolactonization of unsaturated carboxylic acids using iodine and potassium so D.Martin J. A. Wurster M. J. Boylan R.M.Borziileri G.T.Engel and E.J. Walsh TetrahedronLett. 1993,34,8395. Heterocyclic Compounds iodide is well known. Generating the iodine using potassium iodide and sodium persulfate is claimed” to be more convenient faster and higher yielding. 86% Reagents i KH 18-crown-6 THF Scheme 37 The oxidative cyclization of aldehyde (87) is the key step in a synthesiss2 of aranorosin (88) which is also the subject of an independent st~dy.’~ In a related cy~lization’~ oxime (89) gives isoxazoline (90) (Scheme 38).The P-keto-esters (91a) and (91b) react with the propargyl carbonate (92) under palladium(0) catalysis to give furans (93) (Scheme 39).” The 1 -aminobenzotriazole (94) is a precursor of the dihydrobenzofuran (95) when treated with lead tetraa~etate.’~ When N-bromosuccinimide is used as the oxidant the bromo-derivative (96) is formed (Scheme 40). Oxonium ylids are formed from cyclic ethers bearing pendant diazoketones (97) when treated with rhodium(I1). Either [1,2] or [2,3] shifts give oxygen-bridged ring systems (98) (Scheme 41).57 A variety of systems (99) are substituted when treated with 2-haloesters triethyl- borane and air.58 The products (100) are postulated to form via a radical pathway (Scheme 42).The bis(thiophene) (101) exhibits a pronounced solvatochromism;59 yellow in hexane the hue traverses the spectrum to blue in formamide-water. On treatment with fluoride the thiophenes (102a) and (102b) give 2,3-dimethyl- ene-2,3-dihydrothiophene(103)?’ Non-thermal preparations of this reactive inter- mediate are rare (Scheme 43). ” A.C. Royer R.C. Mebane and A.M. Swafford SYNLETT. 1993 899. ’* A. McKillop L. McLaren R. J. Watson R. J. K. Taylor and N. Lewis Tetrahedron Lett. 1993,34 5519. ’3 P. Wipf Y. Kim and P.C.Fritch J. Org. Chem. 1993 58 7195. 54 M. Kacun D. Koyuncu and A. McKillop J. Chem. SOC.,Perkin Trans. I 1993 1771. 55 N.Greeves and J. S. Torode Synthesis 1993 1109. s6 M.A. Birkett D. W. Knight and M. B. Mitchell Tetrahedron Lett. 1993 34 6939. 57 F.G. West T. H. Eberlein and R. W. Tester J. Chem. SOC.,Perkin Trans. 1 1993 2857. ’* E. Baciocchi and E. Muraglia Tetrahedron Lett. 1993 34 5015. 59 F. Effenberger and F. Wurthner Angew. Chem. Int. Ed. Engl. 1993 32 719. 6o K. J. van den Berg and A. M. van Leusen Recl. Trav. Chim. Pays-Bas 1993 112 7. P. W. Sheldrake i CHO NHCOR H Reagents i PhI(OCOCF,), ii H,O,. LiOH Scheme 38 (9la) X = OMe (93) (91b)X = SPh Reagents i HC-CCH,OCO,Me (92). Pd(dbaf -CHCI, dppe Scheme 39 Benzothiophenes (105) having a mercaptopropyl substituent are formed6’ when the dithianes (104) are treated with AIBN/tributyltin hydride (Scheme 44).Cyclic sulfates prepared from 12-diols are known to be usefuI for further transformation of such diols. It has been found that the corresponding cyclic sulfites (often precursors of the sulfates) can be as efficient.62 D.C. Harrowven Tetrahedron Lett. 1993 34,5653. 62 P.H.J. Carlsen and K. Aase. Acta Chim. Scad.. 1993 47 737. Heterocyclic Compounds Reagents i. Pb(OAc),; ii NBS Scheme 40 (97) n= 1,2 (98) Reagents i Rh,(OAc) Scheme 41 (99)X = 0,S. NMe,NH {loo) R = H,Me Reagents i RCHBrCO,Et BEt, air DMSO Scheme 42 (10%) X = "Me3; Y = SiMe3 (10%) X = SiMea; Y = +NEt2Me Reagents i Bu,NF scheme 43 P. W. Sheldrake Reagents i Bu,SnH AIBN Scheme 44 A review of progress in the Fischer indole reaction has appeared.63 A regioselective Fischer indole synthesis is also reported.64The 2form of hydrazone (106) on treatment with diethylaluminium tetramethylpiperidide gives 1,3-dimethyI-2-(2-methylbutyl)-indole (107) in 93% yield whereas the E isomer gave the 2-ethyl-l-methy1-3( 1-methyl)- propyl product (108) in lower yield (42%) but of 93% purity (Scheme 45).OTI-2,+-OTt Me NHN-Ph Me Me (107) (106) (108) Reagents i diethylaluminium tetramethylpiperidide Scheme 45 Keto-amides (109) readily prepared from N-vinyfpyrrolidinone yield cyclic imines (110) on successive acid and base treatment.65 If they are first alkylated the disubstituted products (111) are obtained. (Scheme 46). Reagents i,H,O'; ii NaOH; iii NaH RZX Scheme 46 The iminophosphorane (1 12) can be reacted with isocyanates either to isolate a pyridine (113) or on heating to obtain an aza-indole (114) (Scheme 47).66 The secondary amide (1 15)cyclizes under the action of phosphorus pentachloride to give 3-phenylimidazo[1,5-a]pyridine (116)(Scheme 48).The reaction also works when the amide moiety is attached at the 2-position of a thia~ole.~~ Some mechanistic studies D.L. Hughes Org. Prep. Proced. int. 1993 25 607. 64 E. Maruoka M. Oishi and H. Yamamoto J. Org. Chem. 1993,58,7638. " M.L. Haslego C.A. Maryanoff L. Scott and K. L. Sorgi Heterocycies 1993 35 643. 66 P. Molina E. Aller and M. A. Lorenzo Synthesis 1993 1239. '' T. Benincori E. Brenna and F. Sannicolo J. Chem. SOC. Perkin Trans. I 1993 675. Heterocyclic Compounds 197 were undertaken supporting a nitrile ylid intermediate in a transformation related to the Wallach imidazole synthesis.Reagents i PCl Scheme 48 The novel analgesic epibatidine (117) discovered in the skin of an Ecuadorian frog has been synthesized. Approaches include a Diels-Alder strategy from l-methoxycar- bonyipyrrole,68 and a Heck reaction pyridinating a 7-azabicycio[2.2. Ilhe~tene.~~ H &gC1 H (117) Regeneration of a nitrone from bicycles such as (118)is known. However control of which nitrone is formed can now be obtained7' from variation of the solvent in which the oxidation is carried out (Scheme 49). Isoxazoles (121) can be prepared from acetylenes and nitric acid using a gold catalyst (Scheme50).Trapping experiments using alkenes confirmed that there is an acy1 nitrile oxide inte~mediate.~' 68 D.F. Huang and T.Y. Shen Tetrahedron LPtt. 1993 34,4477. 69 S.C. Clayton and A. C. Regan Tetrahedron Lett. 1993 34,7493. 'O S.A. Ah and M.I.M. Waxer Tetrahedron,1993 49 4339. " F. Gasparrini M.Giovannoli D. Misiti G. Natile G. Palmien and L. Maresca J. Am. Chem. Soc. 1993 115 4401. P. W. Sheldrake i ii -0 HO Reagents i mCPBA CN,CI,; ii mCPBA AcOH Scheme 49 Oximes such as (122) or acyclic examples on treatment with dimethyl carbonate and potassium carbonate give oxazdin-2-ones (123) as indicated (Scheme 51 ).72 0 Reagents i Bu,NAuCI Scheme 50 Scheme 51 Diazo compounds (124)in the presence of a nitrile and rhodium(I1) acetate produce oxazoles (125) (Scheme 52).Homochiral oxazolines are usefu1 chid auxiliaries. The phosphine (126) has been studied in the paIladium-catalysed reaction of alIylic acetates and maionic esters; high yields and enantiomeric excesses up to 99% are The thiazolidine (127)is 72 C.A. Marques M. Sehra P. Tunde and F. Montanari 3. org. Chem. 1993,58 5765. 73 R. D. Conneli M. Tebbe A.R. Ganghoff P. Helquist and B. Akermark Tetrahedron 1993,49 5445. " P. von Matt and A. Pfaltz Aogm. Chem. Int. Ed. Engl. 1993,32 566. '' G.J. Dawson C.G.Frost J. M. J. Williams and S. J. Coote Tetrahedron Lett. 1993,34 3149. Heterocyclic Compounds remarkable as the product of a seven-component c~ndensation.~~ The necessary ingredients are sodium hydrogen sulfide 2-brom0-2-methylpropana1 ammonia 2-methylpropanal carbon dioxide methanol and t-butylisonitrile.The yield is 43%. Reagents i RhJOAc), R2CN Scheme 52 Oximes (128) react with an imidoyl chloride to produce isolable amides (129) (Scheme 53). On heating these amides are transformed to imidazoles ( (129) Reagents i PhC(=NR')Cl; ii H' toluene A scbeme 53 TributyItin-radical-inducedcyclization of the amide (1 31 gives 5-butyl-3-methyl- 3H-imidazo[4,5-c]quinoIin-4[51fl-one (132) via a spirocydic radical intermediate and [1,2 Jacyl shift (Scheme54). Cyclization by a palIadium-cataIysed coupling gives the 1-methyl isomer (t33).78 Treatment of the aryI triazolyl propanol (134)with triphenylphosphine/carbon tetrachloride gives the salt (135) containing the novel SH-6-arylpyrazolo[ 1,2-a] [i,2,4]triazol-4-ium ion (Scheme 55).79 76 A.Domling and I. Ugi Angew. Chem. Znt. Ed. Engl. 1993.32 563. 77 Zhang X. Shui and D.S. Eggleston J. Org. Chem. 1993,58 7092. I. Lantos W.-Y. '* F.Suzuki and T.Kuroda J. Heterocycl. Chem. 1993 30,811. 79 Y.Arredondo R. Pleixats and M.Moreno-Manas Synth. Corn. 1!493,23 1245. P. W. Sheldrake Reagents i Bu,SnH AIBN; ii Pd(UAc) Scheme 54 Scheme 55 4 Six-membered Rings Among the reviews there is an account of the reactivity of 6-unsubstituted 2H-pyran- 2-0nes;~O the synthesis of six- and seven-membered phosphorus heterocycles by ring enlargement is covered,” as is the synthesis of 9-substituted guanines.62 The intramolecular double Michael reaction has been surveyed83 and includes heterocyclic examples; the principle is exempIified in Scheme 56.Scheme 56 There is coverage of the metallation and metal-assisted bond furmation in n-electron-deficient heterocycless4 and there are details of the lithiation of several halogen-substituted pyridines using lithium dii~opropylamide.~~ Lithiation of the pyrimidines (136a) and (136b) has been founds6 to occur at the 5-position using lithium diisopropyIamide but significant furmation of products from 6-lithiation is found with lithium tetramethylpiperidide. With two equivalents of V. Kvita and W. Fischer Chirnia 1993,47,3. ” G. Keglevich Synthesis 1993,931. F.P.Clausen and J. Juhl-Christensen Org. Prep. Proced. lnt. 1993,25,373. 83 M.Ihara and K.Fukurnoto Angew. Chem. lnf. Ed. Engl. 1993,32,1010. 84 K.Undheirn and T. Benneche Acta Chem. Scund. 1933 47 102. G.W. Gribble and M.G. Saulnier Heterocycles 1993,35 151. 86 N. Ple A. Turck P. Martin S. Barbey and G. Queguiner Tetrahedron Lett. 1993,34 1605. Heterocyclic Compounds s-butyllithium a proton can be abstracted from the methyl group of S-hydroxy-2-methylpyridine (137).87If the hydroxy substituent is first protected the approach fails. c1 (136a)X=CI (137) (136b)X = SMe The tactic of introducing temporarily a cornplexing/directing moiety has been applied to the lithiation of pyridine-2-aldehyde.** Electrophiles are introduced in the 3-pusition via the (presumed) complex (139) (Scheme 57). The metallation of iodopyridines is a little more complex.89 Lithiation (lithium diisopropyIamide was used) is ortho-directed by the iodine but a fast migration occurs to give a stabilized iodolithiopyridine from which the product is derived.Thus for example 2-chloro-3- iodopyridine (141) produces 2-chloro-4-iodo-3-substituted products (142) (Scheme 58). Me Reagents i BuLi Me,NCH,CH,N (Me)Li; ii electrophile,E Scheme 57 Reagents:i LDA THF -75 OC; ii electrophile,E Scheme 58 1,2,4-Triazines (143) have been rnetallated at the 6-position using lithium tetra- methylpiperidide," the first examples of metallated triazines. The homochiral stannane (144) on treatment with n-butyllithium at -78 "C gives with retention of configuration the corresponding organolithi~rn,~' which is configurationally stable up to -40°C.87 A. K.Saksena R.G. Lovey V. M. Girijavallabhan H. Guzik and A. K. Ganguly Tetrahedron Let?. 1993 34,3267. 88 T.R.Kelly W. Xu and J. Sundaresan Tetrahedron Lett. 1993,34 6173. 89 P. Rocca C. Cochennac F. Marsais L. Thomas-dit-Dumond M. Mallet A. Godard and G. Qukguiner J. Org. Chem. 1993 58 7832. 90 N. Ple A. Turck G. Queguiner 3. Glassl and H. Neunhoeffer Liebigs Ann. Chem. 1993 583. 91 R.E. Gawley and Q. Zhang J. Am. Chem. Soc. 1993 115 7515. P.W.Sheldrake N,N-Dimethylcinnamide has been reacted photochemically with (145) the first example of a photochemicaf addition to a flavone (Scheme 59).92 Reagents i PhCH=CHCONMe, hv Scheme 59 Pyran-2-ones (149) are produced in moderate to good yields by the reaction of trimethylsilylketene (147) and 1,3-dienes (148) the first examples of [4 + 23 addition of such components.(Scheme 6U).93 c=c=od + rns (147) (148) R' =Me.Meo TMSO; R2= Me.TMS (149) Scbeme 60 Isochroman (150) is converted into an acetal (151) by the action of dichloro-dicyanoquinone in water or methanol (Scheme 61). There are other more complex examples.94 Reagents i DDQI ROH Scheme 61 92 H.C. Hailes R.A. Raphael and J. Staunton Tetrohedron Lett. I993,34 5313. 93 T. Ito T. Aoyama and T.Shirori TetrahedronLett. 1993 34 6583. 94 Y.C.Xu E. Lebeau J.W. Gillard and G. Attardo Tetrahedron Lett. 1993 34 3841. Heterocyclic Compounds Treatment of diazo-ketones (152) with copper complexes (the hexa-fluoroacetylacetonate being the most efficient) gives rise to usefully substituted and functionaIized cyclic ethers (153)? The mechanism involves oxygen insertion of a rnetaI carbenoid fdlowed by rearrangement.Seven- and eight-rnernbered rings are available by the same methodoiogy (Scheme 62). no83% 5 I l-2 Reagents i Cu(hfacac), CH,CI, reflux Scheme 62 Reaction of pyrylium tetrafluoroborate (154) with methylenetriphenylphosphorane followed by deprotonation (n-butyllithium/TMEDA) gives a phosphorane (I 55) which will give six-carbon homologation of aromatic but not enolizable aliphatic aldehydes (Scheme 63).96 Reagents i Ph,P=CH,; ii BuLi TMEDA; iii ArCHO &beme 63 The acrylic ester of salicylaldehyde (157) in the presence of DABCO gives a crystalline coumarin salt (158) (Scheme64).Its isolation confirmsthe hitherto putative intermediate in the Baylis-Hillman reaction.97 Reagents i DABCO CH,Ci Scheme 64 Diazo-ketones (159) on treatment with rhodium@) acetate give cyclic arnino- ” J.S.Clark S.A. Krowiak and L. J. Street Terruhedron Lett. 1993 34,4385. 96 K. Henning and R.J. K. Taylor J. Chem. Soc. Chem. Commun, 1993 1409. 97 S.E Drewes 0.L. Njamela N. D. Emslie N. Ramsar and 3. S.Field Synth. Conunun. 1993.23 2807. P.W. Sheldrake ketones (161) by nitrogen insertion of the carbenoid folIowed by rearrangement of the intermediate (160) (Scheme 65);98compare with the analogous Scheme 62. Reagents i Rh,(OAc) Scheme 55 Oximes of 5-oxoalkanenitriles [(162) R' = Me Et)] have been cyclized with acetyl chloride/acetic anhydride mixtures to give 2-aminopyridine derivatives (163)(Scheme 66).Oximes of 5-oxopentanenitriles[(162) R' = H] gave only glutaronitrile~.~~ In phosphorus oxychloride at 80 "CN-methylformanilide(164) reacts with tertiary amides (165) to give 3-substituted-4-chloroquinulinium salts (166) from which 4-quinolones (167) are obtained by hydrolysis.'*' Yields are generally good (Scheme 67). The formanilide reacts as its Vilsmeier salt and the alkanoamide as an a-chloroenamine. R,&cN i R2JJ"R' NHAc R2 R3 (162) R2. R3= H.aikyl (1s3) Reagents i,AcCl Ac,O Scheme 66 Reagents i RCH,CONMe f165) POCL,; i NaOH Scheme 57 5-Phenylpyrroline-2,3-diones(158) (available from an imine and oxalyf chloride) react with benzyne (from benzenediazoniurn-2-carboxylate) to give 3-phenyl-98 F.G. West and B.N. Naidu J. Am. Chem. Soc. 1993 115 1I77. 99 R.J. Vijn H. J. Arts P.J. Maas and A. M.Castelijns J. Org. Chem. 1993 58 887. loo 0.Meth-Cohn and D. L. Taylor TetrahedronLett. 1993,34,3629. Heterocyclic Compounds isoquinolones (149) (Scheme 68). Mechanistic hypotheses are discussed. Io1 R' I Ph N. R2 A2 0 (168) R' = H,Me,Et; RZ= alkyl phenyl (169) Reagents i benzyne Scheme 68 Both R and S forms of enaminoester (170) are available thus allowing the preparation of (R)-or (S)-2-alkylpiperidines(171) by the protocol' O2 of Scheme 69. (170) (171) Reagents i EtC(O)CH=CH,; ii BH, 50% aq. H,SO,; iii NaBH,CN; iv H, catalyst Scheme 59 Lithiated 2-chloro-Ncycioalkylidene-3-pyridinimines derived from (1 72) react with suitable 0-ethyl thiocarboxylates (173) to give pyrid0[2,3-b][1,5]thiazepines (174) (Scheme 70).A thermally induced ring contraction then gives the 6-arylcycloalka[b] C1,Slnaphthyridines (175) in moderate to good yield.lo3 Ar (175) Reagents i LDA -78°C; ii ArCSOEt (173); iii A Scheme 70 'Of A. Cobes,E. Guitian and L. Castedo J. Org. Chem. 1993,58,3113. lo' R.C. F. Jones I. Turner,and K.J. Howard,Tetruhedron Lett. 1993,34,6329. '03 A. Couture E. Deniau P. Grandclaudron and C. Simion Synthesis 1993 1227. P. W. Sheldrake The nitrobenzene (176) forms a delocalized coloured anion on treatment with sodium hydroxide. As the appropriately localized anion cyclizes onto the nitro group quinoline N-oxides (177) are formed (Scheme 71).lo4 CN CN Reagents i NaOH MeOH scberne 71 6,8-Dioxabicyclo[3.2.lloctanes (1 78) are readily prepared from methyl vinyl ketone and are efficiently transformed into 2,6-disubstituted pyridines (179) by the action of hydroxylamine and aluminium chloride (Scheme 72).'05 Reagents i NH,OH. HCI,AlCI, AcOH Scheme 72 The iminophosphoranes (180) react with or,P-unsaturated aldehydes and the resulting azatriene system gives the pyridines (181) by cyclization and dehydrogena- tion. By contrast if the iminophosphorane is based on furan or thiophene (182) the product is a mixture ofthe (181) analogue together with a fury1 or thienylpyridine (183) (Scheme 73).'06 In the course of a quinocarcin synthesis the phosphonium salt (184) was treated with potassium t-butoxide to produce dihydroisoquinoline (1851 a synthesis claimed to he the first of a dihydroisoquinoline by Wittig methodology (Scheme 74).'*' 2-Chloro-3-oxiranylmethoxypyridine(186) is readily available.Various alcohol amine or hydride nucleophiles open the oxirane ring and subsequent base treatment gives the 3-substituted 2,3-dihydro- 194-dioxino[2,3-b]pyridine system (187) (Scheme 75). I O8 The conformationally restricted Claisen rearrangement of lactone (188) to pipecolic ester (189) forms the key step of a (+)-monomorine synthesis (Scheme 76).'09 The pyrirnidine-2,4-diones f 190a) and (190b) react with certain a,fl-unsaturated Io4 Z. Wrobel A. Kwast and M. Makosga Synthesis 1993 31.lo' J.-G. Jun H.S,Shin and S. H. Kim J. Chem. Soc. Perkin Trans.I 1993 1815. I*' I?. Molina A. Pastor and M. J. Vilaplanu Tetrahedron. 1993 49 7769. lo' P. Garner W.B. Ho and H. Shin J. Am. Chem. Soc. 1993 115 10742 A. Benareb P.Poirot and G. Guillaumet Heterocycles 1993 36 1589. Io9 S. R.Angle and J. G. Breitenbacher Tetrahedron Left. 1993 34,3985. Heterocyclic Compounds acyl-cyanides in a [4 + 21 manner.* lo Acid-catalysed elimination provides a new entry to 5-substituted uraciIs (192) (Scheme 77). R (182) x=o,s Reagents i RCH=CHCHO Scheme 73 (fW Reagents i KOBu' DMF Scheme 74 Reagents i nucleophile;ii NaH. DME Scheme 75 The pyrido[2,3-d-Jpyridazino[2,3-a]indole (194) is a new heterocyclic system.' ' It is prepared by an intramolecular Heck coupling in excellent yidd despite the constraintsof the system precluding an intermediate that can undergo a ciselimination of the palIadium species.A base-catalysed trans eliminationis postulated (Scheme 78). 'lo JX. Zhuo and H. WyIer Helv. Chim. Acta 1993,76 1916. P. Melnyk. J. Gasche. and C. Thal Tetruhedron Lett. 1993,34,5449. P. W.Sheldrake The fused 1,2,5-oxadiazinone (195) reacts with enamines in [4 + 21 fashion followed by elimination of carbon dioxide and amine thus providing a route to unsymmetrical pyrazines (196) (Scheme 79).' 1 Reagents i TIPSOTI; ii 25 "C Scheme 76 0 Reagents :i R'CH=CHCOCN Scheme 77 The 2,4,6-tribromophosphinines(197a) and (197b) undergo palladium-catalysed coupling with 2-trimethylstannylpyrrole,-furan -thiophene or -pyridine all of which substitute at the 2-and 6-positions(Scheme 80),L13 The Z-bmmo substituent can be selectively reduced from (197b) using tributyltin hydride/tctrakis(triphenylphos-phine)palf adium.Flash vacuum pyrolysis of dialkylvinylphosphine gives a 40% yield of phos-phinine,' l4 The synthesis of strychnine has been a popular endeavour;' "A 16.117in particular the application of aza-Cope-Mannich methodology is elegant.' I8*l 'I2 A. Ganesrrn and C.H. Heathcock J. Org. Chem,. 1993,sS,6155 'I3 P.LeFloch D.Cannichaef. L Ricard and F.Mathey J. Am. Chem. Soc. 1993,115 10665. li4 P. kFloch and F. Mathey J. Chem Soc. Chem. Cumrnun. 1993 1295. 'I5 P.Magnus M.Giles R Bonnert G. Johnson L.McQuire M. Deluca A Merritt C.S. Kim,and N. Vicker J. Am. Chem. Soc. 1993 115,81I6. M. E. Kuehne and F.Xu J. Org. Chem. 1993 58 7490. 'I' P. Magnus and M. Giles Tetruhedron Lett. 1993,34,6355. S.R.Angle J.M.Fevig S.D. Knight R.W. Marquis,Jr and L. E+Overman,J.Am. Chem. Soc, 1993,115 3966. S. D. Knight L+E.Oveman and G. Pairaudeau J. Am. Chem. Soc. 1993,115,9293. Heterocyclic Compounds Reagents i Pd(OAc), PPh, K,CO Scheme 78 fjtl Ph Reagents i R’R2NCH=;CHMe Scheme 79 Br 8r (I97a) R = H (198) X 51 0,S NMe (197b)R= Me Reagents:i Pd(dba), Ph,P Scheme 80 P. W.Sheldrake 5 Seven-membered Rings A review of the syntheses of medium-sized rings by ring-expansion reactions includes heterocyclic examples.2o The diene (199) is converted into a dilithium compound with t-butyllithiurn and serves as precursor to a variety of unusual heterocycles,'21 including the first arsepines and bismepines (200) (Scheme 811 the latter of which fM= Bi) has a half-life of only seven minutes. Ph (199) (200)M = P.AS,Sb. Bi Reagents i Bu'Li -80°C; ii PhMCl,; iii TBAF Scheme 81 The bis-cyclopropanated furan (201) isomerizes to 2,3-dihydrooxepine (202) on heating at 130"C. The corresponding anti isomer requires a temperature of 368 "C. Dienophiles react with (201)to give 9-oxabicyclo[4.2.l]nonanes (203) (Scheme82).'22 0 Reagents i 130°C; ii EHC=CHE Scheme 82 The naturally occurring antifungal benzopentathiapin varacin (205) has been synthesized.'23 Intermediate (204) is derived from a benzyne and carbon disulfide and subsequent reaction with disulfur dichloride completes construction of the penta- thiapin ring (Scheme 83).The utility of the displacement reaction of aromatic fluorides is demonstrated by the closure of the oxepine ring to form 6,7-dihydro~l]benzoxepino~4,5-c]quinolin-8(9H)-one (207) from the alcohol (206) (Scheme 84).'24 An intramolecular Heck reaction closes (208)to the dialkylmethylidene-substituted 2,3,4,5-tetrahydro-1H-3-benzazepine (209) (Scheme 85).12 ''O C.J. Roxburgh Tetrahedron Lett. 1993 49 10749. S. Yasuike H. Ohta S. Shiratori,J. Kurita and T. Tsuchiya J. Chem. Soc. Chern. Commun. 1993,1817. 12' T. Golz S.Hamrnes and F.-G. Klarner Chem. Bet. 1993 126,485. lZ3 V. Behar and S.Danishefsky J. Am. Chem. Soc. 1993 115 7017. 124 M. Anzini A. Cappelli and S. Vomero,Heterocycles 1993 36,1065. L. F. Tietze and R. Schimpf Synthesis 1993 875. Heterocyclic Compounds 211 Reagents i S,CI, THF MeOH HCI Scheme 83 ' N OH 'NOH Reagents i NaH DMF 155"C 5 min Scheme 84 Reagents i Pd(OAc), Ph,P KOAc Scheme 85 Radical-mediated ring expansion of (210) gives the benzazepine (211) (Scheme 8S).'z6 The technique was also applied to the preparation of dibenzazepines. Base treatment of (212)was expected to induce ring closure to (213) but this turned out to be the minor (20%) pr~duct;'~' a higher yield (39%) was obtained of (214) resulting from a novel Smiles rearrangement a mechanism confirmed by the isolation of intermediate (215) in 34% yield (Scheme 87).The functionalized azepinone (2 16) on treatment with methyl propiolate gives the aryl pyrrole (217) in high yield.'z8 The mechanism involves cycloaddition an lZ6 Z. B. Zheng and P. Dowd. Tetrahedron Lett. 1993 34 7709. lZ7 J.R. Poudfoot U.R. PateI and S.J. CampbelI J. Org. Chem. 1993 58,699' 12' E. Cartmell J.E. Mayo H. McNab and I.H. Sadler J. Chem. SOC. Chem. Commun. 1993 1417. P. W. Sheldrake aromatization that liberates an a-aminoketone and condensation with a second molecule of methyl propiolate (Scheme 88). dBr CO&t ci (210) Reagents i Bu,SnH AIBN Scheme 86 i QP?Q N CI -Et/ €t (213) Ci (215) Reagents i LiHMDS THF Scheme 87 Reagents i HCECC0,Me Scheme 88 Heterocyclic Compounds The nitrilimine precursor (218) is readily prepared.CycIization gives a 3,3a-dihydro-4H,6H-pyrazolo[1,5-a][4,1 Jbenzoxazepine (219) (Scheme 89). This could be oxidized to the corresponding pyrazole with DDQ. CO Et -KyH I 0 Reagents i NEt, toluene reflux Scheme 89 The reaction of 2-aminothiophenol(220) with various 241-haloaIky1)oxiranes(221) provides a convenient synthesis of lY5-benzothiazepins(222) (Scheme 90)' 30 Reagents i NEt,; ii KOH Scheme 90 On exposure to Mitsunobu conditions dithioketals (223) give ring-expanded products (224) via 1,3-sul€urmigration (Scheme 91 (223) m=n=1,2 (224) Reagents i DEAD Ph,P THF Scheme 91 Dihydrothiepin-1,l-dioxide(225) can be lithiated and reacted with electrophiles.The products (226) are convenient precursors to trienes (227) (Scheme 92). 129 L.Garanti G. Zccchi and L. Bruche J. Heterocycl. Chem. 1993 559. 130 M.Karikorni S. Yamori and T. Toda Heterocycles 1993 35 519. 13* S.Takano H.Iida. and K.Ogasawata Heterocycles 1993 36,2203. J.H. Rigby and A.C. Kruger SYNLETT. 1993 829. P.W. Sheldrake Reagents i Bu"Li HMPA -105 "C;ii electrophile E; iii 175 "C Scheme 92 6 Larger Rings There is a review of improved methods for the synthesis of aza-crown macrocycles and crypt and^.'^^ Two accuunts'34-13J of the biosynthesis of vitamin B, have appeared. B-Methoxyborinanes(228)react with a-chloroallyllithiurn to give after treatment of the initial adduct with boron trifluoride the B-rnethoxyboracydenes (229) (Scheme 93).I 36 OMe (228) n=0-7 Reagents i CH,=CHCH,Cl LiNR, -78°C; ii BF,.Et,O; iii -78"+r.t Scheme 93 Pyrido[l,2-a]azepinone (230)is deprotonated in the pyridine ring by LDA and the lithiated species will react with a variety of electrophiles.When an aldehyde is used the intermediate alkoxide attacks the lactam giving [7)(2,6)pyridinophane (231) (Scheme 94).13' (230) Reagents i LDA; ii RCHO Scheme 94 J33 K. E. Krakowiak J.S. Bradshaw and R.M. Izatt SYNLETT. 1993,611. 13* A. I. Scott Angew. Chem. int. Ed. Engl. 1993,32,1223. 13' A.R. Battersby Acc. Chem. Res. 1993 26 15. 136 H. C.Brown and S. Jayaraman Tetrahedron Lett. 1993 34,3997. 13' W. Maier M. Keller and W. Eberbach Heterocycles 1993,35 817.Heterocyclic Compounds The N-oxide (232) is converted in methanol under reflux into 3,6-epoxyhexahyd- roazocino[5,4-b]indole (233) (Scheme 95). A radical pathway is suggested.’38 Reagents i 90% MeOH Irradiation of the j?-ketovinylogous amide (234) leads to formation of the acetylpyrrole (237). Formation of the stabiIized diradical (2351 which can form keto-irnine (2361 is a likely mechanism (Scheme 96).13’ I I / Reagents i hv scheme % The thionocarbonate (238)was treated with base to form the cyclic thionocarbonate (239) which by [3,3] sigmatropic ring expansion gave thiolcarbonate (240) (Scheme 97).14* This material was converted into yellow-scale pheromone. The subtlety of the experiments needed to elucidate the biosynthesis of haem and vitamin B (see Chapter 11)tends to obscure the underlying synthetic work.The key step in the preparation of the spiro compound (244) was the combination of ’” T.Kurihara Y. Sakamoto M. Takai K. Ohuchi,S. Harasawa and R. Yoneda Chem. Pkorm. Bull. 1993 41 1221. 139 J.D. Winkltr and M.G.Siegel Tetrahedron Lett. 1993 34 7597. S. Harusawa S. Takemura H. Osaki R. Yoneda and T. Kurihara Tetrahedron 1993,49 7657. P. W. Sheldrake iododihydrodipyrrin (241) with the pyrrole (242) to give the lactam (243) (Scheme 98);14'methodology developed specificalIy for this target. The ultimate target was the octaacid corresponding to (244) required for use in enzyme inhibition studies. Reagents i LiHMDS scheme 97 Reagents i SnC14 CH,Cl,; ii AgOAc TsOH THF H,O Scheme 98 14' W.M.Stark C.J. Hawker G.J. Hart A. Phitippides P.M.Petersen J. D. Lewis F. J. Leeper and A. R. Battersby J. Chem. SOC.,Perkin Trans. I 1993 2875.

ISSN:0069-3030    

DOI:10.1039/OC9939000179

出版商:RSC    

年代:1993

数据来源: RSC