7 Aromatic Compounds By R. McCAGUE Drug Development Section Institute of Cancer Research Clifton Avenue Sutton Surrey SM2 5PX 1 General and Theoretical Studies Benzene.-There is controversy over the fundamental problem of the origin of the exceptional stability of aromatic compounds. Cooper et al. challenge the molecular orbital description that the r-electrons in benzene are delocalized. Using a spin- coupled valence bond description they arrive at six non-orthogonal orbitals each highly localized about a carbon nucleus. The aromatic stabilization is then explained by a particularly favourable symmetric coupling of the electron spins around the carbon framework.' A further area of dispute concerns the distortive propensity of the .rr-system of benzene.In reply to criticisms2 regarding the validity of chosen bond lengths Hiberty et al. consolidate their argument by comparison with a hypothetical molecule H6 that the symmetrical r-components of benzene are unstable with respect to distortion towards a Kikult type of ~tructure.~ The observed symmetrical structure of benzene is then explained by the tendency of the 0-framework to achieve bond equalization being greater than the tendency of the r-system to cause distortion. This latter tendency is weak in aromatic systems but strong in non-aromatic olefins. A real and strong KCkulC type distortion of benzene is observed using electron diffraction when it is co-adsorbed with carbon monoxide onto the surface of a rhodium cry~tal.~ Each benzene molecule is bonded to three rhodium atoms the extent of distortion (C-C bond lengths 1.81 and 1.33 A) indicating partial transfor- mation into three molecules of acetylene.It is thought that the electron acceptance by the co-adsorbed carbon monoxide promotes the distortion of the benzene molecule and hence that carbon monoxide might catalyse the benzene-acetylene interconversion on rhodi~m.~ Low-temperature photolysis of the benzene trimer (1)5 generated the benzene dimer (2) which has a lifetime of ca. 0.5 s at ambient temperature. Flash photolysis studies of dimer (2) give a free energy of activation AG* = 15.7 kcal mol-' for its decomposition into benzene. Kinetics of the decomposition of the more stable adducts of benzene with anthracene and naphthacene revealed A G values extending over a range that indicated a synchronous bond-breaking proce~s.~ This,conclusion ' D.L. Cooper J. Gerratt and M. Raimondi Nature (London) 1986 323 699. N. C. Baird J. Org. Chem. 1986 51 3907. P. C. Hiberty S. S. Shaik G. Ohanessian and J.-M. Lefour J. Org. Chem. 1986 51 3908. M. A. Van Hove R. F. Lin and G. A. Somorjai 1.Am. Chem. Soc. 1986 108 2532. A. Bertszh W. Grimme and G. Reinhardt Angew. Chem. Int. Edn. Engl. 1986 25 377. 147 148 R McCague is in apparent conflict with MNDO calculations6 that predict the dimerization of benzene would occur by a pathway with asynchronous formation of the new a-bonds. The benzene-carbon monoxide adduct (3) has also been synthe~ized.~ It decomposes into benzene and carbon monoxide with a similar activation energy as that for the dimer (2).The decompositions of compounds (2) and (3) have the lowest energies yet observed for a retro-Diels- Alder reaction. Measurements of gas-phase heats of formation of the keto tautomers of phenol (4) and (9,show the linearly conjugated dienone (4) to be the more stable by 4 kcal mol-'.8 Kinetic measurements of the conversion of the dienone (4) into phenol revealed that (4) is a strong carbon acid pK -3 f 1 the tautomerization being dominated by protonation of water although below pH 3 the tautomerism is acid catal ysed.' b Calculated geometries of phenyl and benzyl radicals (see Figure 1) show that in the phenyl radical (6) the bonds to the carbon bearing the unpaired electron are shortened relative to those in benzene and in the benzyl radical (7)the ring bonds to the substituted carbon are lengthened." The unusual bonding in benzynes and cyclopropabenzenes attracts theoretical study.Ab initio molecular orbital calculations give the bond lengths shown in Figure 1 for o-benzyne (8) the short C-1 to C-2 bond length indicating extensive overlap of the in-plane sp2-type orbitals. The similarity of the remaining C-C bond lengths is evidence against wbond fixation in o-benzyne." In addition to evidence for the existence of free o-benzynes," m-and p-benzynes have been generated by thermoly- ses of polymer-bound diaryliodonium carboxylates followed by trapping onto a R. Engelke J. Am. Chem SOC.,1986 108 5799. D. M. Birney and J.A. Berson Tetrahedron 1986 42 1561. * C. S. Shiner P. E. Vorndam and S. R. Kass J. Am. Chem. Soc. 1986 108 5699. M. Capponi I. Gut and J. Win Angew. Chem. Int. Edn. Engl. 1986,25 344. J. Pacansky B. Liu and D. DeFrees J. Org. Chem. 1986 51 3720. 10 " L. Radom R. H. Nobes D. J. Underwood and W.-K. Li Pure Appl. Chem 1986 SS 75. '* F. Gavina S. V. Luis A. M. Costero and P. Gil Tetrahedron 1986 42 155. Aromatic Compounds 1 49 second resin containing a bound n~cleophile.’~ The results support the expected biradical structure for m-and p-benzynes. Molecular orbital calculations (both semi-empirical and ab initio methods) have been made for cy~lopropabenzene.’~ The semi-empirical methods gave erroneous geometries but the geometries calculated by ab initio methods are in good agreement with experiment a calculated structure being given in Figure 1.The bond angles around the bridge are severely distorted but there is little 7r-bond fixation. The observed reactivity at the bridge carbon atoms is explained by the localization of the HOMO at the bridge bond. 1.387 \H 1.384\H 1.493 1.390 1.380 - H 1.371 1.071 1.396 1.073 1.392 1.383 Figure 1 Calculated geometries ofthe phenyl radical (6),the benzyl radical (7) o-benzyne (8) and cyclopropabenzene (9). Bond lengths are in A A variety of papers lead to an improved understanding of the effect of substituents on the benzene nucleus. A simple algorithm for the calculation of nionization energies in polysubstituted benzenes based on the HOMO approach has a~peared.’~ Calculations on benzyl-type carbanions have led to a re-emphasis of the concept of resonance saturation whereby the electron release of CH2- and OMe is not additive the effect being particularly important if the substituents are para.16 Mag-netic circular dichroism (MCD) of the benzene bond has been shown to give a measure of the net 7r-electron donor and acceptor properties of a substituent and proves particularly useful as a probe for hyperconjugative power.” Evidence for negative hyperconjugation by methyl groups in anilines and anisoles (i,e +B Ar-X-CH3 Ar-X+=CH2 H-; X = 0 NH NMe) has been found from the long-range deuterium isotope shifts observed for a para fluorine in the fluorine-19 n.m.r.spectrum.18 Studies of encumbered symmetrically hexasubstituted benzenes c6&,have been reported by Mislow et al.Hexaisopropylbenzene has been shown to have an excep- tionally rigid structure with gear-meshed isopropyl groups requiring 35 kcal mol-’ for their rotation.” Hexakis(dimethylsily1)benzene on the other hand has a much lower rotational barrier of 14.2 kcal mol-’ indicating a stepwise mechanism for its homomerization.” Unlike hexaisopropylbenzene which has essentially c6 sym-metry in the crystal the trimethylgermyl analogue R = Ge(CH,) had a slightly l3 F. Gavina S. V. Luis V. S. Safont P. Ferrer and A. M. Costero Tetrahedron Lett. 1986 27 4779. 14 Y. Apeloig and D. Arad J. Am. Chem. SOL,1986 108 3241. 1s J. Cioslowski A. Baranski and T.Juska Tetrahedron 1986 42 4549. 16 G. Vanermen S. Toppet M. Van Beylen and P. Geerlings J. Chem SOC.,Perkin Trans. 2 1986 699. 17 G. H. Weeks W. Adcock K. A. Klingensmith J. W. Waluk R. West M. Vasak J. Downing and J. Michl Pure Appl. Chem. 1986 58 39. 18 D. A. Forsyth and J.-R. Yang J. Am. Chem. SOC,1986 108 2157. 19 J. Siegel A. Gutierrez W. B. Schweizer,0.Ermer and K. Mislow J. Am. Chem. SOC.,1986 108 1569. 20 I. I. Schuster W. Weissensteiner and K. Mislow J. Am. Chem. SOC.,1986 108 6661. 150 R. McCague puckered benzene ring with germanium atoms located alternately above and below the average ring plane.21 Calculations on the unsynthesized hexa-t-butyl and hexakis( trimethylsilyl) analogues predict that these will also have a D3 symmetry.21 Homoaromaticity.-Homoaromaticity in Cations.The homotropylium ion ( 10) with its cyclic 6.n conjugated system can be regarded as the archetypal homoaromatic system. Scott and Hashemi have addressed the question of whether it has an ‘open’ form with through-space overlap of p-orbitals at the homoconjugation gap or whether it is ‘closed’ with the conjugation completed by cyclopropane Walsh orbitals.22 The close similarity of the physical properties of this ion with the synthesized bridged homotropylium ion (11)that is constrained into a ‘closed’ form has led to their conclusion that the unconstrained ion (10) must have a relatively small homoconjugation gap of 1.5-1.7 A.22In contrast the ethoxyhomotropylium ion (f2) the structure of which has been solved by X-ray diffraction has an ‘open’ conformation with a C1-C7 internuclear distance of 2.28 8 and bond length alterna- tion suggesting that this ion is better represented as a linear 1-ethoxyoctatrienyl cation than as an aromatic system.23 Nonetheless the presence of ring current in the n.m.r.spectrum of (12) shows that there is still homoconjugation. The use of one-bond 13C-13C coupling constants as a measure of carbon atom hybridization has been demonstrated and applied to the bis-homotropylium ion (13); the results support an earlier conclusion that the ion is homoaromatic having partial three- membered rings rather than being a localized ally1 cation (14).24 The formulation of certain radical cations as bis-homoaromatic has been made for the first time by Roth and Abelt for structures such as (15)25and (16).26In the case of (16) the neutral hydrocarbon undergoes retrocyclization to generate the tetraene (17) from which it was originally prepared.Neutral Homoaromaticity. The evidence for cyclic homoconjugation by its imparting non-alternant character to alternant hydrocarbons has been reviewed.” However 21 W. Weissensteiner I. I. Schuster J. F. Blount and K. Mislow J. Am. Chem. Soc. 1986 108 6664. 22 L. T. Scott and M. M. Hashemi Tetrahedron 1986 42 1823. 23 R. F. Childs R. Faggiani C. J. L. Lock and M. Mahendran J. Am. Chem. Soc. 1986 108 3613. 24 G. Jonsall and P. Ahlberg J. Am. Chem. Soc. 1986 108 3819. 25 H. D. Roth and C. J. Abelt J. Am. Gem. Soc. 1986 108 2013.26 C. J. Abelt and H. D. Roth J. Am. Chem. Soc. 1986 108 6734. 27 L. T. Scott fire Appl. Chem. 1986 58 105. 151 Aromatic Compounds whether homoaromaticity can be used to describe a neutral system has remained a matter of debate. Although n.m.r. spectroscopy shows that the 9-phosphabarbaralene (18) has a localized structure the closeness of the bond lengths of C-2-C-8 and C-4-C-6 (1.949 and 2.054 A respectively) as found by X-ray diffraction was taken as evidence for this being the closest approach to a neutral bis-homoaromatic system yet found.28 Neutral bis-homoantiaromaticity has been claimed for the biphenylene (19) on the basis of spectral evidence which points to significant homoc~njugation.~~ The possibility of tris-homoaromaticity in structure (20)has been discounted since its photoelectron spectrum can be accounted for by the large separation (2.60A) between the doubly bonded carbon atoms (as revealed by X-ray cry~tallography).~~ The prevention of adequate .rr-orbital overlap by the a-framework in this and similar structures has been recognized in a computational eval~ation.~~ However using thermochemistry rather than spectroscopy to detect aromaticity comparison of the heat of hydrogenation of triquinacene (21) with its partially saturated analogues indicates that triquinacene has a significant albeit small degree of homoaromatic- Lastly the possibility of homoaromaticity in hexaethynylbenzene owing to overlap of the orthogonal ethynyl .rr-orbitals has been raised but there is as yet no experimental evidence to support such an interacti01-1.~~ Homoaromaticity in Anions.There has been active debate concerning whether the anion from bicyclo[3.2.l]octa-2,6-diene (22) owes its stability to bis-homo- aromaticity. New support for a homoaromatic structure has been based on n.m.r. data34 and gas-phase physical measurement^.^^ The crystal structure of the 28 S. A. Weissman and S. G. Baxter J. Am. Chem. Soc. 1986 108 529. 29 C. F. Wilkox Jr. D. A. Blain J. Clardy G. Van Duyne R. Gleiter and M. Eckert-Maksic J. Am. Chem. SOC.,1986 108 7693. 30 J. E. McMurry G. J. Haley J. R. Matz J. C. Clardy G. Van Duyne R. Gleiter W. Schafer and D. H. White J. Am. Chem. SOC.,1986 108 2932. 31 A. B. McEwen and P. von R. Schleyer J.Org. Chem. 1986 51 4357. 32 J. F. Leibman L. A. Paquette J. R. Peterson and D. W. Rogers J. Am. Chem. SOC.,1986 108 8267. 33 R. Diercks J. C. Armstrong R. Boese and K. P. C. Vollhardt Angew. Chem. Int. Edn. Engl. 1986 25 268. 34 M. Christ1 and D. Bruckner Chem. Ber. 1986 119 2025. 35 R. E. Lee and R. R. Squires J. Am. Chem. SOC.,1986 108 5078. 152 R. McCague tetramethylethylenediamine complex of the lithium salt has been solved and shows co-ordination of the lithium cation to both the olefinic bond and ally1 anion as depicted in (23) and in doing so reduces the homoconjugation distance to 2.37 On the basis of these observations it is all the more interesting that an independent MCSCF molecular orbital study has predicted that the stability could be due to electrostatic association with the cation rather than to hom~aromaticity.~' More recent MNDO calculations agree with this hypothesis but it has been pointed out that even in the absence of a lithium gegenion the stabilization of the anion can be accounted for by negative hyperconjugation and inductive effects as are docu- mented for the homoallyl anion (24).38 Thus it seems unlikely that there is any significant homoaromaticity in (23).Capitalizing on this controversy Huber and Mullen claim in a review" that their 10~ dianion (25) represents a better case for homoaromaticity than does (23). 2 Synthesis of Substituted Benzenes From Non-aromatic Precursors.-In a series of papers Vollhardt et al. have applied their cobalt complex catalysed cyclization of acetylenic units.For example trimeriz- ation of diisopropylacetylene gave hexais~propylbenzene.'~ Linear [4]phenylenes of interest for their alternation between 4n and 4n + 2 total T electrons with increasing length were prepared as shown in Scheme 1. Since the trialkyltin groups could be converted into ethynyl functions the reaction sequence could in principle be continued indefinitely possibly to give polymers with useful electrical conducting proper tie^.^' A similar strategy gave angular [4]phenylene~.~'~~* Probably the most elegant application has been a single step assembly of a B-ring aromatic steroid framework from an acyclic precursor.43 Scheme 1 36 N. Hertkorn F. H. Kohler G. Muller and G. Reber Angew.Chen Int. Edn. Engl. 1986 25 468. 37 R. Lindh B. 0. Roos,G. Jonsall and P. Ahlberg J. Am. Chem Soc. 1986 108 6554. 38 P. von R. Schleyer E. Kaufmann A. J. Kos H. Mayr and J. Chandrasekhar J. Chem SOC Chem. Commun. 1986 1583. 39 W. Huber and K. Mullen Acc. Chem Res. 1985 19 300. M.Hirthammer and K.P. C. Vollhardt J. Am. Chem. SOC 1986 108 2481. 41 R. Diercks and K. P. C. Vollhardt Angew. Chem. Int. Edn. EngL 1986 25 266. 42 R. Diercks and'K. P. C. Vollhardt J. Am. Chem. Soc. 1986 108 3150. 43 S.H.Lecker N. H. Nguyen and K. P. C. Vollhardt J. Am. Chem. SOC. 1986 108 856. Aromatic Compounds 153 Diels-Alder cyclization is an obvious route for the synthesis of benzene rings but is relatively little used for monocyclic systems. However Diels- Alder reaction with methyl propiolate has been used in a novel benzannulation sequence (Scheme 2).44 Scheme 2 Biomimetic polyketide condensations such as that shown in Scheme 3;’ are proving attractive for the synthesis of aromatic rings in precursors of antitumour antibiotics such as Frederi~amycin.~~ ] -COzMe _&C02Me [&zMe &2Me c-COzMe COzMe COZMe Scheme 3 Cyclocondensations related to the Robinson annelation followed by aromatization have been used to synthesize aryl ~ulphides~~ and the fully substituted benzene ring in certain phenolic natural products:* In a curious synthesis of metu-substituted aromatic compounds addition of an alkyllithium to a tricyclic ketone is followed by Lewis acid catalysed rearrangement of the carbinol and then oxidative aromatiz- ation (Scheme 4).49 0 0 xqR-;bQL CHO CHO Scheme 4 Electrophilic Substitution.-Mechanistic Studies.Remarkably the detailed mechan- ism of as fundamental a reaction as aromatic nitration is still not fully established. According to MNDO calc~lations,~~ for compounds such as toluene and xylene the Wheland intermediate is formed by way of an electron transfer (i.e. ArH + NO2++ArH+’ + NO;) followed by radical-pair combination and only when the aromatic ring bears electron-withdrawing groups is the classical direct electrophilic attack by NO2+the only mechanism. However there is the conflicting experimental 44 R.L. Snowden and M. Wust Tetrahedron Lett. 1986 27 703. 45 M. Yamaguchi K. Hasebe and T.Minami Tetrahedron Lett. 1986 27 2401. 46 K. A. Parker and G. A. Breault Tetrahedron Lett. 1986 27 3835. 47 T. H. Chan and C. V. C. Prasad J. Org.Chem. 1986 51 3012. 48 H. Saimoto and T. Hiyama Tetrahedron Lett. 1986 27 597. 49 J. Adams and M. Belley J. Org.Chem 1986 51 3878. 50 J. Feng X.Zheng and M.C. Zerner J. Org. Chem. 1986 51,4531. 154 R. McCague evidence that independently-generated arene radical cations react with nitrogen dioxide to give a different isomer product distribution than is observed during normal nitration suggesting a radical-pair mechanism is not in~olved.~’ Moreover only with radical cations having an electron potential >1.7 V (e.g. naphthalene but not perylene) can a successful (exergonic) coupling with nitrogen dioxide take place.Nonetheless in the case of nitrous acid-catalysed nitration of p-nitrophenol the proposed mechanism is oxidation of the substrate to the phenolate radical which then combines with nitrogen dioxide.52 The discovery that nitration can be accom- plished in the gas phase using protonated methyl nitrate will hopefully assist experimental studies of nitration mechani~rns.~~ The matter of merging stepwise (electron transfer) and concerted (electrophilic) mechanisms is also a feature of the reaction of arenes with the active electrophiles Hg(OAc) or Tl(O,CCF,),+. These reactions have been shown to proceed via observable ~r-complexes.~~ Synthetic Procedures. ips0 -Protonation by sufficiently strong acids can effectively redirect an electrophilic substitution reaction allowing the rearrangement of nitrocompounds by [1,3] shifts to thermodynamically more stable isomers55 and allowing the acylation of arenes by transfer of the acetyl function from acetylpen- tamethylben~ene.~~ The specific reduction of unhindered nitro-groups by sulphide allows the synthesis of nitroarenes which cannot be prepared dire~tly,~’ such as the synthesis of hexanitrobenzene from trinitrotol~ene.~~ Electrophilic attack can be redirected by blocking the favoured site of attack with a t-butyl group that can be later removed by transalkylation with excess benzene and aluminium chloride.59 With the increasing demand for specifically fluorinated arenes new reagents have emerged for aromatic fluorination and.these have been reviewed.60 Iodoarenes can be prepared by replacement of trimethylsilyl using iodine and silver tetrafluoro- borate.61 Regiospecific p-halogenation of phenols has been achieved using tetrabutyl- ammonium tribromide6 or halodimefiylsulphonium halides.63 In a useful synthesis of aromatic aldehydes N,N-dimethylbenzylamines (ArCH2NMe2) are prepared either by reaction of phenols with formaldehyde- dimethylamine,@ or from aryltributylstannanes with Eschenmoser salts (Me N+=CH2 Cl-),65 and are then treated with hexamethylenetetraamine and acid.@ 51 L.Eberson and F. Radner Acta Chem. Scand. Ser. B 1986,40 71. 52 M. Ali and J. H. Ridd J2 Chem. SOC.,Perkin Trans. 2 1986 327. 53 M. Attina and F. Cacace 1. Am. Chem SOC,1986 108 318.54 W. Lau and J. K. Kochi J. Am. Chem SOC.,1986 108,6720. 55 P. Barrow J. V. Bullen A. Dent T. Murphy J. H. Ridd and 0.Sabek J. Chem SOC Chem. Commun. 1986 1649. 56 T. Keumi T. Mortia T. Shimada N. Teshima H. Kitajima and G. K. S. hakash J. Chem Soc. Perkin Trans. 2 1986 847. ” T. E. Nickson J. Org. Chem. 1986 51 3903. 58 R. L. Atkins R. A. Hollins and W. S. Wilson J. Org. Chem. 1986 51 3261. 59 S. Kajigaeshi T. Kadowaki A. Nishida and S. Fujisaki Bull. Chem. SOC. Jpn. 1986 59 97. 69 S. T. Pumngton B. S. Kagen and T. B. Patrick Chem. Rev. 1986 86 997. 61 S. R. Wilson and L. A. Jacob J. Org. Chem 1986,51 4833. J. Bethelot C. Guette M. Ouchefoune P.-L.Desbene and J.-J. Basselier J. Chem. Res. (S),1986 381. 63 G. A. Olah L.Ohannesian and M. Arvanaghi Synthesis 1986 868. 64 M. T. Clark and D. D. Miller J. Org. Chem 1986 51 4072. 65 M. S. Cooper and H. Heaney Tetrahedron Lett. 1986,27 5011. Aromatic Compounds 155 Direct chemical hydroxylation of arenes can be difficult. Anilines have been hydroxylated using hydrogen peroxide in superacid the electrophile being H302+.66 Benzene has been converted into phenol by electroreduction of dioxygen in tri- fluoromethanesulphonic acid,67 and under conditions of hydroxyl radical gener- ation.6s Microbial oxidation can also sometimes take place readily and regioselective para-hydroxylation by the fungus Beauoeria sulfurexens has been reported.69 Intramolecular electrophilic cyclization using aryliodonium tetrafluoroborates has been used to prepare dihydr~naphthalenes~' and functionalized tetrahydronaph- thalenes the latter by using episulphoni~m~' intermediates or episelenoni~m~~ derived from alkenes.Nucleophilic Substitution.-Mechanistic Studies. The nucleophilic substitution reac- tion has attracted many kinetic studies. In the reaction of l-chloro-2,4-dinitrobenzene with piperidine hydrogen bonding between the 2-nitro-group and the nucleophile favours the reaction so that increasing the hydrogen-bond-donating ability of the solvent decreases the reaction rate.73 When amines are the nucleophiles it has been found that non-nucleophilic bases catalyse the reaction indicating that the rate- limiting step is then deprotonation of the initial reversibly-formed zwitterionic a-~omplex.~~ Furthermore it has been suggested that a significant decrease in rate when a bulkier amine is the nucleophile is likely to be due to a lower rate of this proton-transfer rather than to a lower rate of the initial nucleophilic attack.75 Consequently the use of a hydrogen-bond-accepting solvent such as DMSO can increase the rate of such a reaction.An alternative viewpoint is that the effective nucleophile could consist of a hydrogen-bonded dimer (or higher ~ligomer).'~ Nucleophilic aromatic substitution can be catalysed by P-cyclodextrin the rate enhancement being due to reversible nucleophilic displacement by the cyclodextrin in addition to formation of an inclusion complex.77 It is now well established that metal carbonyl rr-complexation dramatically increases the rate of nucleophilic attack on the aromatic ring.A relationship has been reported connecting the reactivity with the stretch force constant of the carbonyl bonds in the metal carbonyl having the arene replaced by carbon monoxide.78 Synthetic Procedures. Nucleophilic attack is often fastest at unsubstituted ring posi- tions. Exploitation of this feature has led to the most significant latest developments in nucleophilic aromatic substitution since a change in the substitution pattern of the ring can be brought about. In the case of arenetricarbonylchromium complexes 66 J.-C. Jacquesy M.-P. Juannetaud G. Morellet and Y. Vidal Bull. SOC.Chim. Fr. 1986 625. 67 R.Ohnishi and A. Aramata J. Chem. Soc. Chem. Commun. 1986 1630.68 A. Kunai S. Hata S. Ito and K. Sasaki J. Am. Chem. SOC.,1986,108,6012; J. Org. Chem. 1986,51,3471. 69 B. Vigne A. Archelas J. D. Fourneron and R. Furstoss Tetrahedron 1986,42 2451. 70 M. Ochiai Y.Takoaka K. Sumi and Y. Nagao J. Chem. SOC.,Chem. Commun. 1986 1382. 71 E. D. Edstrom and T. Livinghouse J. Chem. Soc. Chem. Commun. 1986,279; J. Am. Chem. Soc. 1986 108 1334. 72 E. D. Edstrom and T. Livinghouse Tetrahedron Lett. 1986 27 3483. 73 R. D. Martinez P. M. E. Mancini L. R. Vottcro and N. S. Nudelman J. Chem. SOC.,Perkin Trans. 2 1986 1427. 74 E. Buncel C. Innis and I. Onyido J. Org. Chem. 1986 51 3680. 7s N. S.Nudelman and S. Cerdeira J. Chem. SOC.,Perkin Trans. 2 1986 695. 76 0. Banjoko and C. Ezeani J. Chem. SOC.,Perkin TrunJ.2 1986 531. 77 R.H. de Rossi M. Barra and E. B. de Vargas J. Org. Chem. 1986,51 2157. 78 R. C. Bush and R. J. Angelici J. Am. Chem. Soc. 1986 108 2735. 156 R. McCague acid treatment of the initial adduct causes elimination of the proton at the attack site together with a leaving group. Accordingly tele-and cine-substitutions have been achieved (Scheme 5).79 The leaving group can be benzylic as in the reaction of benzyl alcohol tricarbonylchromium with alkyllithiums to give o-alkyltoluenes.80 Replacement of hydrogen ortho to a nitro-group in nitrobenzenes by the nucleophile Me3 SiCH2 MgCl is accomplished after DDQ oxidation of the initial adduct.’* R R Y tele-Substitution cine-Substitution favoured if X is electron-favoured if X is electron-releasing (e.g.OPh) withdrawing (e.g. C1) X-= leaving group Y-= nucleophile Scheme 5 Radical Substitution.-Radical cyclization by aryl radicals onto a double bond in the same molecule was observed following treatment of the arenediazonium tetra- fluoroborates with copper saltsg2 or by U.V. photolysis of the aryl iodide^.'^ The 2-nitropropane anion has been shown to be a powerful nucleophile in its addition to electrochemically generated aryl radicals giving overall replacement of halide.84 Homolytic arylation of aromatic compounds to give biphenyls has been reviewed.” Substitution uia Transition Metal a-Complexes.-The use of transition metal com- plex catalysis for bringing about selective substitutions at sp2 centres has made a very significant contribution to the advancement of organic synthesis in recent years.Typically using palladi~m-~’~~~’~ catalysts useful features and cobalt-9~g6complex of the methodology are the ready route to carbonyl-substituted arene~’~*’~-’~ (owing to a facile insertion of carbon monoxide into the initially formed aryl-metal a-bond) and the fact that in addition to halides triflates can be di~placed~~.’~ allowing overall ’9 F. Rose-Munch E. Rose and A. Semra J. Chem. SOC.,Chem. Commun. 1986 1108 and 1551. SO J. Blagg S. G. Davies C. L. Goodfellow and K. H. Sutton J. Chem. SOC.,Chem. Commun. 1986 1283. 81 G. Bartoli M. Bosco R. Dalpouo and P. E. Todesco J. Org. Chem. 1986,51 3694. 82 G. F. Meijs and A. L. J. Beckwith J. Am Chem. SOC. 1986 108 5890. 83 A. N. Abeywickrema and A.L. J. Beckwith Tetrahedron Lett. 1986 27 109. 84 C. Amatore M. Gareil M. A. Oturan J. Pinson J.-M. Saveant and A. Thiebault J. Org. Chem. 1986 51 3757. 85 R. Bolton and G. H. Williams Chem SOC.Reu. 1986 15 261. 86 Q.-Y. Chen Y.B. He and Z.-Y. Yang J. Chem SOC.,Chem. Commun. 1986 1452. 87 N. Miyaura T. Ishiyama M. Ishikawa and A. Suzuki Tetrahedron Lett. 1986 27 6369. ’* D. A. Widdowson and Y.-Z. Zhang Tetrahedron 1986 42 2111. 89 T. R. Bailey Tetrahedron Lett. 1986 27 4407. 90 A. Dondoni M. Fogagholo G. Fantin A. Medici and P. Pedrini Tetrahedron Lett. 1986 27 5269. 91 V. P. Baillargeon and J. K. Stille J. Am Chem. SOC 1986 108 452. 92 E. Neigichi and J. M. Tour Tetrahedron Lett. 1986 27 4869. 93 S. Cacchi P.G. Gattini E. Morera and G. Ortar Tetrahedron Lett. 1986 27 3931. 94 T. Kashimura K. Kudo S. Mori and W. Sugita Chem. Lett. 1986 851. 95 T. Kashimura K. Kudo S. Mori and N. Sugita Chem. Lett. 1986 299. % M. Miura F. Akase and M. Nomura J. Chem. SOC.,Chem. Commun. 1986 241. Aromatic Compounds 157 replacement of the hydroxyl group of phenols. An outline of the course of these reactions is shown in Scheme 6. Examples of groups that can be introduced in this way are H,86 alk~l,~~ heter~aryl,~~ for-ary1,88 alkyn~l?~ 2,2-dimethyloxazolinyl~0 my1?* alko~ycarbonyl~~*~~ carboxylic acid,95 and methyl ketone?6 In addition the method has been used in a cyclization to form naphthoq~inones.~' .,-ArCO-[MI-X 2ArCOY ArX -% Ar-[MI-X where X = halogen or triflate and [MI represents the transition metal and associated ligands Scheme 6 Metallation with a manganese carbonyl complex has been used to introduce electrophiles into the ring position adjacent to a methyl ketone gr0up.9~ Phenylation of amines phenols and enols has been reported using triphenylbismuth diacetate?* Substitution vita Lithiation.-Several advances have been made in the area of regiocontrol of lithiation.Reaction of tetramethyldopamine with alkyllithium gives selective lithiation at either of the two vacant ring positions depending on whether the treatment is at -78°C or room temperature.- The remaining position can be specifically substituted using palladium acetate mediated cyclometallation.99 Regio- specific lithiation ortho to fluorine in tricarbonylchromium-complexed fluoroanisoles has allowed the synthesis of a range of polysubstituted arenes.Im In contrast the uncomplexed arenes give preferred lithiation ortho to the methoxy group.'o' The use of tertiary P-aminobenzamides [ArCON( Me)CH2CH NMe,] for directed lithiation has the advantages that the amide function is easily hydrolysed or can be treated to give improved yields of aldehydes or ketones compared with other dialkylamides.'02 Lithiation of N-monoalkylanilines can be achieved by prior in situ conversion into the N-carb~xylate.'~~ A procedure for substitution ortho to the amino group in N,N-unsubstituted anilines is via the lithium salt of the formamide the formyl group being readily removed by hydrolysis.'" Substitution uh Arynes.-The formation of a substituted benzyne by elimination of iodine and fluorine from the readily prepared 2-iodo-3-fluoroanisole has found use in the synthesis of conformationally defined tricyclic tyramine analogue^.'^^ Jung and Lowen have demonstrated the intramolecular coupling of anions and benzyne both generated using lithium diisopropylamide (LDA).The method was used in a direct synthesis of an intermediate for podophyllotoxin synthesis.'06 Buchwald et 97 L. H. P. Gommons L. Main and B. K. Nicholson J. Chem. SOC Chem Commun.,1986 12. 98 D. H. R. Barton J.-P. Finet J. Khamsi and C. Pichon Tetrahedron Lett. 1986 27 3615 and 3619; D. H. R. Barton N. Y. Bhatnagar J.-P. Finet and W. B. Motherwell. Tetrahedron 1986 42 3111. 99 C.D. Liang Tetrahedron Lett. 1986 27 1971. loo J. P. Gilday and D. A. Widdowson Tetrahedron Lett. 1986 27 5525. 101 J. P. Gilday and D. A. Widdowson J. Chem. SOC,Chem. Commun. 1986 1235. 102 D. L. Comins and J. D. Brown J. Org. Chem. 1986. 51. 3566. 103 A. R. Katritzky W. Q. Fan and K. Akutagawa Tetrahedron 1986,42,4027. 104 I. Fleming M. A. Loreto I. H. M. Wallace and J. P. Michael J. Chem. SOC.,Perkin Trans. I 1986,349. 105 G. L. Grunewald H. S. Arrington W. J. Bartlett T. J. Reitz and D. J. Sall J. Med. Chem. 1986,29 1972. lo6 M. E. Jung and G. T. Lowen Tetrahedron Lett. 1986 27 5319. 158 R. McCague al. have begun to uncover a rich chemistry of the zirconocene-benzyne complex (26); examples showing its great promise as a precursor to substituted benzenes are its coupling reactions with acetone and diethylacetylene (Scheme 7).'07 E:m a ,EtCECEt CP2Q I PMe3 Et (26) Scheme 7 Other Reactions.-Treatment of arenediazonium salts with formamide has been shown to effect reduction to the arene the proposed mechanism being cleavage of the formyltriazene in a six-membered ring transition state resulting in the elimination of nitrogen and HNC0.'08 3 Benzene Derivatives for the Synthesis of Non-aromatic Compounds Reductions.-The application of the Birch reduction for the synthesis of natural products has been reviewed."' In contrast to previous observations benzonitriles and N,N-dialkylbenzamides have been shown to be excellent substrates for the Birch reduction and reductive alkylations.' lo Phenyl radical cations generated by electroreduction have been trapped intramolecularly by a ketone function to give cyclized products with high diastereoselectivity; Scheme 8 gives an example."' Scheme 8 A reversal of the regi9selectivity of the Birch reduction has been achieved using photolysis in the presence of an electron acceptor 1,3-dicyanobenzene and sodium borohydride.Typically the least substituted 1,4-diene is formed. The mechanism for this 'Photo-Birch' reduction of p-xylene is illustrated in Scheme 9.112 H Me Me Me Me 04.0 -22% Q /. 0 \ DCB DCB*--DCB-^ DCB + H+ Me Me H Me H Me DCB = 1,3-dicyanobenzene Scheme 9 107 S. L. Buchwald B. T. Watson and J. C. Huffman J. Am. Chem. SOC.,1986 108 7411.108 M. D. Threadgill and A. P. Gledhill J. Chem. Soc. Perkin Trans. I 1986 873. 109 J. M. Hook and L. N. Mander Nut. hod. Rep. 1986 3 35. 110 A. G. Schultz and M. Macielag J. 0%.Chem. 1986 51 4983. Ill T. Shono N. Kise T. Suzumoto and T. Morimoto J. Am. Chem. SOC.,1986 108 4676. 112 G. A. Epling and E. Florio Tetrahedron Let?. 1986 27 1469. Aromatic Compounds meto-Photocyc1oaddition.-Mechanistic studies of the meta-cycloaddition to arenes have been concerned with rationalizing the observed regioselectivity in terms of a dipolar intermediate. Investigation of the isotope effects of deuterium incorporation into the arene indicate that the electron cloud of the photoexcited arene becomes polarized on approach of the alkene as postulated in Scheme the stabilization of this induced charge separation influences the regi~selectivity."~-' l4 Alternatively the regioselectivity can be explained by orbital symmetry consideration^."^ Scheme 10 The stereocontrol found in the final ring formation when the 2v-component is trans- 1,2-dichloroethene is attributed to distortion of the biradical bicyclic inter- mediate induced by the chlorine atoms.' l6 The rneta-cycloaddition reaction has been employed in a total synthesis of the complex seven-membered ring anti-leukaemic agent rudmollin."' Thermal Cyc1oaddition.-Benzene derivatives do not normally undergo Diels- Alder reactions with olefins but following observations that addition of N-phenyl-maleimide to phenols can take place a theoretical approach has predicted that the reaction will occur only if the olefin is strained."' Interestingly a remarkably facile Diels-Alder addition to a benzene ring has been found (Scheme 11) where intramolecular hydrogen bonding holds the molecule in a favourable conformation for cycl~addition."~ C0.NHR' 80 "C ___ R' Scheme 11 4 Polyhalogenoarenes One of the characteristics of polyhalogenoarenes is the ease with which they form radical species; this is considered to be an important factor in the environmental 113 P.de Vaal G.Lodder and J. Cornelisse Tetrahedron 1986 42 4585. 114 J. Mattay J. Runsink J. Gersdorf T. Rumbach and C. Ly,Helv. Chem. Acta 1986 69 442. I15 D. Bryce-Smith A. Gilbert and J. Mattay Tetrahedron 1986 42 6011.I16 J. Cornelisse A. Gilbert and P.W. Rodwell Tetrahedron Lett. 1986 27 5003. 117 P.A. Wender and K. Fisher Tetrahedron Lett. 1986 27 1857. 118 J. Arriau J. Fernandez and P. Yianni J. Chem. SOC. Perkin Trans. 2 1986 2013. 119 K. Diehl and G. Himbert Chem. Ber. 1986 119 3812. 160 R. McCague problems associated with polychloroarenes. Oxidation of perfluoroarenes by dioxy- genyl tetrafluoroarsenate (02+ASF6-) gives radical cation salts; that formed from perfluoronaphthalene is stable.’” Radical cations of polychlorinated biphenyls have been observed under pulse irradiation conditions.’” Studies of the radical anion of perchlorobenzene [PCB-Cl+’] reveal two pathways of its fragmentation to PCB’ and C1- or to PCB- and Cr.’” Photolysis of pentafluorophenyl ally1 ether gives intramolecular [2+ 21cycloaddi-tion to form a tricyclic str~cture.’’~ Such tricyclic compounds might be intermediates in the photo-Claisen rearrangement.Although a characteristic of perfluoroarenes is their propensity to attack by nucleophiles displacement of fluorine by certain nucleophiles that are ‘soft’ in hard-soft acid-base theory is not favoured. Thus Grignard reagents displace cyanide and from 1,4-dicyan0-2,3,5,6-tetrafluorobenzene~~~ do not affect perfluorotolyl ethers.’25u Also octafluorotoluene arylates the caesium enolate of androst-Cene- 3,17-dione at oxygen instead of at carbon.’25b 5 Condensed Polycyclic Aromatic Compounds Theoretical Studies.-MNDO calculations on closed-loop odd-alternant polycyclic polyenes such as the phenalenyl system show that there is a genuinely non-bonding frontier .rr-orbital and consequently the Huckel (4n+ 2) rule does not apply for these systems.’26 Early in the year a report by Haymet appeared re-emphasizing the predi~tion’~~ that the intriguing hypothetical icosohedral c60 hydrocarbon ‘footballene’ (‘Buck- minsterfullerene’) would be stable with a spherically delocalized 7r-system having a high Huckel delocalization energy (DE) of 0.55P/carbon compared to a value of 0.33Plcarbon for benzene.’’* Other calculations have also been reported’29a and predicts that the molecule would not undergo bond distortions to optimize energy and would therefore maintain a symmetrical structure.However it has been pointed out that the Huckel DE used by Haymet is not a good criterion for stability.A better one is resonance energy per welectron (REPE) for which footballene gives a value of 0.031p compared to 0.065 for benzene 0.038 for pentacene and 0.022 for an infinite polyacene so that an REPE of the size found does not guarantee stability.’30 MNDO calculations for the automerization of naphthalene indicate that tetracyclic ‘valene’ derivatives are probably not involved and a new mechanism in which benzofulvenes are intermediates has been I?”. T. J. Richardson F. L. Tanzella and N. Bartlett J. Am. Chem Soc. 1986 108 4937. 121 J. Monig K.-D. Asmus L. W. Robertson and F. Oesch J. Chem. Soc. Perkin Trans. 2 1986 891. P. K. Freeman R. Srinivasa J.-A. Campbell and M.L. Deinzer J. Am. Chem. Soc. 1986 108 5531. 123 B. Sket N. Zupancic and M. Zupan Tetrahedron 1986 42 753. 124 D. J. Milner 1. Organomet. Chem. 1986 302,147. 125 (a) R. McCague J. Chem. Res. (S) 1986 58; (b) M. Jarman and R. McCague J. Chem. Soc. Chern. Commun. 1986 635; (c) C. Glidewell and D. Lloyd J. Chem Rex (S) 1986 106. ’*’ D. A. Bochvar and E. G. Gal’pern Dokl. Akad. Nauk SSSR 1973 209 610. 12* A.D. J. Haymet J. Am. Chem Soc. 1986 108 319. 129 (a) D. J. Klein T. G. Schmalz G. E. Hite and u’. 4. Seitz J. Am Chem. Soc. 1986 108 1301; (b) M. D. Newton and R. E. Stanton J. Am. Chem. SOC,1986 108,2469; (c) M. Kataoka and T. Nakajima Tetrahedron. 1986. 42. 6437. 130 €4. A. Hess jun. and L. J. Schaad J. Org. Chem. 1986 51 3902.13‘ M. J. S. Dewar and K. M. Merz jun. J. Am. Chem. SOC.,1986 108 5146. Aromatic Compounds 161 Synthesis of Condensed Aromatic Compounds.-From Acyclic Precursors. The total synthesis of the E-rhodomycinone racemic anthracyclone has been accomplished by way of a polyketide c~ndensation.'~~ A useful feature of the reaction (shown in Scheme 3) is that the product is like the starting material a glutarate and the reaction sequence can be repeated to give polyoxygenated polynuclear linear a~enes.4~ Using Diels- Alder Reactions. Utilization of the Diels-Alder approach to polycyclic systems is currently very popular much of the work having been aimed at the synthesis of anthracycline antibiotic^'^^-'^^ such as daunomycine. Frequently used When quinones 2n-components are the and benzyne~.'~-'~~ are used regioselectivity can be brought into the cyclization by substitution of the quinone double bond with such groups as CN SPh or C1.Typical 4n-components and furans136~138~139~144-'47.'50 used are quin~dimethanes'~~.'~~ although a variety of polarized simple butadienes have also been an example being 3-chloro-l-methoxy-1,3-butadiene which has been used in an efficient synthesis of the naphthalene 5-lipoxygenase inhibitor RS-43 179.l4O The use of 1,2-dimethyl- enecyclohexanes has also been rep~rted.'~~ The basic components can be benzo- fused allowing highly convergent syntheses of structures having several rings to be undertaken. Thus naphtho[ 1,2-c]furan and naphtho[2,3-c]furan which have now been ~ynthesized'~~.'~~ can be used for annelation of a phenanthrene and anthracene unit respectively.Also a 1-(dialky1amino)isobenzofuranreacts with a variety of 27r-components allowing direct aromatic-ring annul at ion^.'^^ Other Methods of Ring Construction. A novel sequence for 2,3-naphthalene annula- tion from acyclic or cyclic ketones is illustrated in Scheme 12.'51 0-Allylbenzamides cyclize on formation of the anion with methyllithium to give a regioselective synthesis 132 K. Krohn and W. Priyono Liebigs Ann. Chem. 1986 1506. 133 Y. Tamura M. Sasho S. Akai and H. Kishimoto Tetrahedron Lett. 1986 27 195; R. A. Russell R. W. Irvine and R. N. Warrener J. Org. Chem. 1986 51 1595. 134 G.A. Kraus and J.A. Walling Tetrahedron Lett. 1986 27 1873. 135 D. W. Cameron C. Conn. M. J. Crossley G.I. Feutrill M. W. Fisher P. G. Griffiths B. K. Merrett and D. Pavlatos Tetrahedron Lett. 1986 27 2417; D. W. Cameron G. I. Feutrill P.G. Griffiths and B. K. Merrett ibid. p. 2421. 136 R. W. Franck V. Bhat and C. S. Subramaniam J. Am. Chem. Soc. 1986 108,2455. 137 A. A. Abdallah J.-P. Gesson J.-C. Jaquesy and M. Mondon BulL SOC.Chim Fr. 1986,93; A. Bekaert J. Andrieux. and M. Plat ibid. 314. 138 J.-G. Smith P. W. Dibble and R. E. Sandborn J. 0%.Chern. 1986 51 3762. I39 W. C. Christopfel and L. L. Miller J. Org. Chem. 1986 51 4169. 140 D. L. Flynn and D. E. Nies Tetrahedron Lett. 1986 27 5075. 141 M. S. Newman and V. K. Khanna J. Org.Chem 1986,51 1921.142 A. D. Thomas and L. L. Miller J. Org. Chem 1986,51,4160; L. L. Miller A. D. Thomas C. L. Wilkins and D. A. Weil J. Chem. SOC.,Chem. Commun. 1986 661. 143 G.A. Kraus and S. H.Woo,J. Org. Chem 1986 51 114. 144 F. Gavina S. V. Luis P. Ferrer A. M.Costero and P. Gil Tetrahedron 1986 42 5641. 145 D. J. Pollart and B. Rickborn J. Org. Chem 1986 51 3155. 146 R. Camezind and B. Rickborn J. Org. Chem. 1986 51 1914; J. Netka S. L. Crump and B. Rickborn ibid. p. 1189. 147 H. Hart and D. Ok J. Org. Chem. 1986 51,979. 148 J. Makayama M. Kuroda and M. Hoshino Heterocycles 1986,24,1233; R. G.Carlson K. Srinivasachar R. S. Givens and B. K. MatuszEwski J. Org.Chem. 1986 51 3978. 149 R. D.Bach and R. C. Klix Tetrahedron Lett. 1986 27 1983. 1so C.-W.Chen and P. Beak J. Org. Chem. 1986 51 3325. M. A. Tius and J. Gomez-Galeno Tetrahedron Lett. 1986 27 2571. 162 R. McCague of naphthols and naphthoq~inones.'~~ 9-Phenanthrols are obtained on ring-expansion of (a-bromobenzyl)fluorenols.'53A rapid synthetic approach to sub- stituted chrysene derivatives involves alkylation of the lithium salt of 1,Cdime- thoxycy~lohexadiene.~~~ Reagents i PhCH2MgC1 -55 "C; ii pyridinium tosylate; iii TiC14 CH2C12 Scheme 12 Preparation of SpecificaZZy Substituted Products. One approach to the substitution of arenes at certain sites that are unaffected by electrophilic reagents is to functionalize a precursor of the arene having different positional reactivity. This strategy is employed in the synthesis of 2,7-dibromopyrene via electrophilic substitution in 4,5,9,10-tetrahydr0pyrene'~~ and in a synthesis of 2,3-disubstituted anthracenes by electrophilic substitution in 9,10-ethano-9,10-dihydroanthracenefollowed by flash vacuum thermolytic elimination of eth~1ene.l~~ The observed reactivity in the ethanoanthracene is attributed to hybridization changes at the ring junction owing to ring strain.A new synthesis of 2,3-dibromonaphthalene useful as a synthon for extended trypticines from 1,2,4,5-tetrabromobenzenevia the potentially versatile intermediate (27) is shown in Scheme 13.'57 Reagents i Bu"Li (1 equiv.) furan; ii TiC14 Zn THF Scheme 13 Carcinogenicity of Polycyclic Aromatic Hydrocarbons (PAH).-It is now established that bay region diol epoxides are the ultimate carcinogenic metabolites of PAH.In a review of the structural requirements favouring tumourigenicity of methylated PAH generalizations made are that a methyl group in a bay region adjacent to an unsubstituted ring increases tumourigenicity (+B effect) whereas substitution of a peri-position adjacent to the angular ring decreases it (-P effe~t)."~ Following a synthesis of diol epoxides of 5-methylchrysene the diol epoxide (28) has been 152 M. P. Sibi. J. W. Dankwardt. and V. Snieckus. J. Org. Chem. 1986 51 271. A. Tantivanich and D. Supatimusro Tetrahedron Lett. 1986 27 5301. I54 R. G. Harvey J. Pataki and H. Lee J. Org. Chem. 1986 51 1407. 155 H. Lee and R. G. Harvey J. Org. Chem. 1986 51 2847. I56 J. E. Baldwin A.G. Swanson J. K. Cha and J. A. Murphy Tetrahedron 1986.42 3943. 15' H. Hart A. Bashir-Hashemi. J. Luo. and M. A. Meador Tetrahedron 1986 42 1641. 158 S. S. Hecht A. A. Melikian and S. Amin Acc. Chem. Res. 1986 19 174. Aromatic Compounds confirmed to be the Jltimate carcinogen from the hydrocarbon; n.m.r.studies show the hydroxyl groups to prefer a diequatorial on formation.'^^ Similarly diol epoxides (29) have been synthesized and shown to be the principle active carcinogenic metabolites of 7,12-dimethylbenz[ ~lanthracene.'~~ A review has also appeared on the synthesis of oxidized metabolites of PAH including the dihydrodiols.'60 Resolution and absolute-configuration determinations of various PAH dihy-drodiols and epoxides reveal that usually the dihydrodiols having RR-stereochemistry are dextrorotatory in the case of K-region diols and laevorotatory in the case of bay-region diols and that these are the preferred enantiomers formed metabolically by rat liver rnicrosomes.l6' Novel Polycyclic Structures.-Planar Structures.The cycloarene (30) has been synthe- sized. The chemical shift of the inner protons (8 9.56) shows that despite the inner and outer 4n + 2 welectron peripheries there is no annular ring-current although the localization of aromatic sextets is thought to be less than in kekulene.'62 The cyclohexa[ cdlperylium ion [31] a higher homologue of the phenalenium ion showed a strong induced n.m.r. ring-current indicating an extensively delocalized struct~re.'~~ The hexagonal planar 13-ring hydrocarbon hexaperibenzocoronene has been suggested as being abundant in interstellar media and a new synthesis has been pre~ented.'~~ (30) (31) 159 H.Lee and R. G. Harvey J. Org. Chem. 1986 51 3502. 160 R. G. Harvey Synthesis 1986 605. 161 J. M. Sayer P. J. van Bladeren H. J. C. Yeh and D. M.Jerina J. Org. Chem. 1986 51 452; S. K. Balani P. J. van Bladeren N. Shirai and D. M. Jerina ibid. p. 1773; M. Schollmeir H. Frank F. Oesch and K. L. Platt ibid. p. 5368. 162 D. J. H. Funhoff and H. A. Staab Angew. Chem. Znt. Edn. Engl. 1986,25 742. 163 K. Yamamura H. Miyake and I. Murata J. Org. Chem. 1986 51 251. 164 W. Hendel Z. H. Khan and W. Schmidt Tetrahedron. 1986 42 1127. 164 R. McCague Triptycenes.Extended triptycenes (iptycenes) have been of interest for their high melting points (with consequent possibilities for use as thermoresistant materials) and because their molecular cavities should allow complexation of other molecules. A variety of iptycenes have been ~ynthesized.'~~~'~~ Helicenes. Some elegant work on helicenes has been published by Katz et al. The synthesis of [7]helicenes has been improved by the use of a bromine-substituted precursor (32). The bromine atom directs photocyclization in the manner required to give the helicene.'66 In an asymmetric synthesis of a helicene the configuration of the carbon marked by an asterisk in precursor (33) controls the wind of the helix in the resulting photocyclization the bulky silyl group becoming placed outside the heli~.'~' Cobalt complexation of helicenes terminating in cyclopentadienyl units could lead to optically active polymers possibly with unusual electrical magnetic and optical properties.16' Twisted Hydrocarbons.The diphenyltetrabenzanthracene (34) has been shown by X-ray diffraction to be twisted by 66" spread along the anthracene structure. The helicity of (34)along the planes of the rings is in contrast to the helicenes where the twist is perpendicular to the ring ~1anes.l~~ Distortion of the geometry of the anthracene rings in 1,8-diarylanthracenes causes unexpectedly low barriers to rota- tion of the aryl gro~ps."~ 16' A. Bashir-Hashemi H. Hart and D. L. Ward J. Am. Chem. Soc. 1986 108 6675. 166 A. Sudhakar and T. J. Katz Tetrahedron Lett.1986,27 2231. 167 A. Sudhakar and T. J. Katz J. Am. Chem. Soc. 1986 108 179. A. Sudhakar. T. J. Katz. and B.-W. Yang J. Am. Gem. Soc.. 1986 108 2790. 169 R. A. Pascal jun. W. D. McMillan and D. Van Engen J. Am. Chem. Soc. 1986 108 5652. 170 H. 0. House J. A. Hrabie and D. VanDerveer J. Org. Chem 1986,51 921. Aromatic Compounds 165 6 Cyclophanes Distortion of the Benzene Ring.-Probably the best compounds for studying the effects of distortion of aromatic rings are the simple [nlparacyclophanes preparable by U.V. irradiation of corresponding Dewar benzenes. [SIParacyclophane (35 n = 5) is a highly unstable species but substitution by ester and methyl groups increases the ~tabi1ity.l~~ The X-ray crystal structure of a derivative of [6]paracyclophane reveals the expected severe distortion of the benzene rings into a boat c~nformation.'~~ A consequence of this distortion in [6]paracyclophane itself are the facile addition reactions with N-phenyltriazolinedione or bromine oxidation with m-chloroperoxy- benzoic acid and thermal rearrangement to a spirotriene (36 n = 6) presumably uia benzylic bond horn~lysis,'~~ In contrast conditions of flash vacuum thermolysis can be used to prepare [7]- and [8]-paracyclophane from the appropriate spirotrienes (7 and 80% yields respecti~ely).'~~ 2-[6]Paracyloph-3-ene (37) has been prepared; U.V.evidence suggests an increase in the benzene ring distortion compared with [6lparacyclophane.174 Using a new method for establishing the degree of aromaticity based on measure- ments of quadrupolar couplings in the deuterium n.m.r.spectrum [5lmetacyclo-phane is shown to be fully aromatic despite its strongly distorted ring.'75 Ring Interactions.-U.v. irradiation of quadruple-layered cyclophanes gave revers- ible formation of a cage structure between the central rings. The outer rings are thought to stabilize the cage ~tructure.'~~ Syntheses have been reported of syn- [2.2]metacyclophanes (38) and (39). The former was prepared from trithia p3]-(1,3,5)~yclophane'~~ and the latter by ring-contraction of a chromium-complexed dithia prec~rsor.'~~ Both rearrange to the anti-conformer with an activation energy of ca. 20 kcal mol-'. A strong anchimeric assistance to the ionization of the tosylate (40) during acetolysis has been attributed to a T-T interaction between the rings as indicated.179 171 G.B. M. Kostermans W. H. de Wolf and F. Bickelhaupt Tetrahedron Lett. 1986 27 1095. 172 Y. Tobe K.-I. Ueda K. Kakiuchi Y. Odaira Y. Kai and N. Kasai Tetrahedron 1986 42 1851. 173 L. W. Jenneskens W. H. de Wolf and F. Bickelhaupt Tetrahedron 1986,42 1571. 174 Y. Tobe K.-I. Ueda K. Kakiuchi and Y. Odaira Angew. Chem. Znt. Edn. Engl. 1986 25 369. 175 P. C. M. van Zijl L. W. Jenneskens E. W. Bastiaan C. MacLean W. H. de Wolf and F. Bickelhaupt J. Am. Chem. Soc. 1986 108 1415. 176 H. Higuchi E. Kobayashi Y. Sakata and S. Misumi Tetrahedron 1986 42 1731. 177 Y. Fujise Y. Nakasato and S. Ito Tetrahedron Lett. 1986 27 2907.178 R. H. Mitchell Pure Appl. Chem. 1986 58 15. '79 J. Nishimura Y. Okada and A. Oku J. Org. Chem. 1986 51 1838. 166 R. McCague Macrocyclophanes.-[2.2.2]Paracyclophane (41) forms a stable dianion but which is neither paratropic nor diatropic since steric requirements force one ring at any given time to be out of plane of the remaining delocalized system."' Large-ring [9 to 151 paracyclophanes have been prepared by the photolysis of large-ring 2-phenylcycloalkanones the mechanism being homolysis adjacent to the carbonyl group and recombination at the para-position on the benzene ring.'81 Encapsulation within a zeolite matrix can improve this process.'** Macrocyclophanes have been of interest for the synthesis of [3]~atenanes,'~~ and those with three linking chains for the study of conformational interconversions of the chain position which can occur by a chain passing either between or over the aromatic rings.'84 Other Studies.-Features of the absorption spectra of cyclophanes have been re~iewed.'~'The possibility of forming organic electrical conductors by linking [2n] cyclophane units to give a one-dimensional polymer has been explored using ruthenium copper or silver complexation to link the units.'86 Also by connecting together anthracene units the resulting v-orbital interactions between adjacent units might enable the construction of organic erni icon duct or^.'^^ [2.2]Metacyclophanes where one chain is longer than the other owing to heteroatom substitution have helicity.The enantiomers are separable and may be useful for chiral induction of chemical reactions.'" 7 Non-benzenoid Aromatic Systems Theoretical Studies.-Haddon has demonstrated using v-orbital axis vectors analy- sis (POAV) that rehybridization of the orbitals in bridged annulenes can improve v-bonding overlap.189 The rehybridization is particularly large at the 4-position of 180 D.Tanner 0.Wennerstrom U. Norinder K. Mullen and R. Trinks Terrahedron 1986 42 4499. 181 X. Lei C. Doubleday jun. and N. J. Turro Tetrahedron Lett. 1986 27 4675. X.-G. Lei C. E. Doubleday jun. M. B. Zimmt and N. J. Turro J. Am. Chem. Soc. 1986 108 2444. K. Rissler G. Schill H. Fritz and W. Vetter Chem. Ber. 1986 119 1374. I84 A. B. Brown and H. W. Whitlock jun. J. Am. Chem.Soc. 1986 108 3509. 185 J. Ferguson Chem. Rev. 1986 86 957. 186 R. T. Swann A. W. Hanson and V. Boekelheide J. Am. Chem. Soc. 1986 108 3324; R. H. Voegeli H. C. Kang R. G. Finke and V. Boekelheide ibid. p. 7010; V. Boekelheide Pure Appl. Chem. 1986 58 1; H. Schmidbaur W. Bublack B. Huber G. Reber and G. Muller Angew. Chem. IN. Edn. Engl. 1986,25 1089. 187 J. Fiedler W. Huber and K. Mullen Angew. Chem. Znt. Edn. Engl. 1986 25 443; D. Bender H. Unterberg and K. Mullen ibid. p. 444. 188 F. Vogtle J. Struck H. Puff P. Woller and H. Reuter J. Chem. Soc. Chem. Commun. 1986 1248. 189 R. C. Haddon J. Am. Chem. Soc. 1986 108 2837; R. C. Haddon and L. T. Scott Pure Appf. Chem. 1986 58 137. Aromatic Compounds 1,4,7-methino[ l01annulene (42) and explains the high degree of aromaticity in this annulene.For cyclic 4n-anions a relationship has been established between the proton n.m.r. ring-current anisotropy with the ratio of carbon-1 3 n.m.r. chemical shifts and charge.'" Ab initio molecular orbital calculations of 4n-annulenes by Haddon indicate that only cyclobutadiene exhibits a strong resonance destabilization and surprisingly the hypothetical planar cis-[ 12lannulene would have a small positive resonance energy.'" Interestingly heat of hydrogenation measurements of the fused system (43) a [4n]annuleno[4n)annulene indicate a positive resonance energv. suggesting delocalization around the [4n + 21 periphery in variance with theoretical predi~tions.''~ Studies of [4n + 2]annuleno[4n + 2lannulenes such as (44) indicate that delocalization in the neutral hydrocarbons is governed by the two subunits but by the monocyclic perimeter in ionic Non-alternant Fused-ring Systems.-A new mechanism for the azulene to naphthalene rearrangement proposed by Dewar and Men.from MNDO and MIND0 calculations is shown in Scheme 14.'94 Scheme 14 Studies by Hafner et al. on the 127r hexamethylheptalenes e.g. (45) which exist as optical isomers owing to twisting by the eclipsed methyl groups have shown them to exhibit a barrier to both racemization and bond rearrangement in the order of 20-30 kcal m~l-'.'~~ Derivatives of cyclohepta[ eflheptylene reveal a similar bond rear rang ern en^'^^ (45) (46) 190 B. Eliasson U. Edlund and K. Mullen J.Chem. Soc. Perkin Trans 2 1986 937. 191 R. C. Haddon Pure Appl. Chem. 1986 58 129. I92 W. D. Roth H.-W. Lennartz E. Vogel M. Leiendecker and M. Oda Chem. Ber. 1986 119 837. 193 W. Huber. K.Mulllen C. Schneiders M. lyoda and M. Nakagawa Helu. Chim. Am 1986. 69 949. 194 M. J. S. Dewar and K.M. Merz,jun. J. Am. Chem. SOC.,1986 108 5142. 195 K. Hafner and G. L. Knaup Tetrahedron Lett. 1986 27 1665. 196 K. Hafner G. L. Knaup and H. J. Linder Angew. Chem. Int. Edn. Engl. 1986 25 633. 168 R. McCague Small-ring Aromatic Cations.-Despite the inherent stability of the cyclopropenyl cation it is stabilized by welectron donating substituents such as amino or hydroxyl groups. Electron-withdrawing groups are de~tabilizing.'~~ The cyclopropenyl cation is also stabilized by out-of-plane cyclopropyl substituents and in-plane phenyl groups.19* The remarkably stable pagodane dication (46) is obtained simply by prolonged chlorosulphonylfluoride-antimony pentafluoride treatment of the hydro- carbon.Its structure can be rationalized as a 2-electron aromatic system with the worbitals in the plane of the ring. Calculations indicate a rectangular structure with bond orders of ca. 1.5 and 0.5.'99 Higher Annu1enes.-The anion of the bridged biphenylene (19) is found to possess a 10~ aromatic system the inner proton resonating at S -2.79.200 9b-Methyl-9bH- benz[ cdlazulene (47) a 12.rr-electron system has been synthesized the methyl group having been introduced by methylation of 4,5-dihydro-3H- benz[ cdlazulene.Antiaromaticity is evident from the S 4.75 resonance of the central methyl group.*'' Reductive methylation of aceheptylene occurs at the inner angular carbon allowing the synthesis of a range of annulenes with novel .rr-perimeters; examples are the strongly diatropic hydrocarbons (48) and (49).202 A consequence of the asymmetry of hydrocarbons such as (47)-(49) is that one of the bond-shift forms can be favoured over the other. Thus the form (47) is that favoured and bond fixation reduces the diatropicity of (48). Vogel et al. have reported the synthesis of syn-and anti-bismethano[ 14lannulenes which have a phenanthrene perimeter.203 The syn-isomer (50) is diatropic but less so than the anthracene analogue; the anti-isomer has olefinic properties owing to the high torsional angles.Quinones of homoazulene (1,5-methano[ l01annulene) had U.V. spectra like those of quinones derived from azulene rather than an alternant hydrocarbon illustrating the homoconjugative interaction in these quinones.2" Properties of the radical anion of 1,5-methano[ lO]annulene are also attributed to a homoconjugative intera~tion.~~' 197 A. C. Hopkinson and M. H. Lien J. Am. Chem. SOC.,1986 108 2843. 198 R. A. Moss S. Shen K. Krogh-Jespersen J. A. Potenza H. J. Schugar and R. C. Munjal J. Am. Chem. SOL,1986 108 134. 199 G. K. S. F'rakash V. V. Krishnamurthy R. Herges R. Bau H. Yuan G. A. Olah W.-D. Fessner and H. Prinzbach J. Am. Chem. SOL,1986 108 836. 200 C. F. Wilcox jun. and D. A. Blain Tetrahedron 1986 42 6389.20 I K. Hafner and V. Kuhn Angew. Chem. Znt. Edn. En@ 1986 25 632. 202 G. Neumann and K. Mullen J. Am. Chem. SOC.,1986 108 4105; K. Mullen Pure Appl. Chem. 1986 58 177. 203 E. Vogel W. Puttmann W. Duchatsch T. Schieb H. Schmicker and J. Lex Angew. Chem. Znt. Edn. Engl. 1986 25 720; E. Vogel T. Schieb W. H. Schulz K. Schmidt H. Schmickler and J. Lex ibid. p. 723. 204 L. T. Scott and M. Oda Tetrahedron Lett. 1986 27 779. 205 F. Gerson J. Knobel A. Metzger L. T. Scott M. A. Kirms M. Oda and C. A. Sumpter J. Am. Chem SOC.,1986 108 7920. Aromatic Compounds The paratropic doubly bridged [24]annulene (51) has been synthesized uia Wittig condensations and reductive coupling.206 A series of related methano-bridged bis- dehydro [181 [ZO] [22] and [24]-annulenes were found to be paratropic or diatropic depending on the number of ~-electrons,~~~ but a series of bisdehydrodibenzo-annulenes were neither dia- nor paratropic,208 presumably owing to bond fixation by the benzo-fusion.The [24]annulene (52) was prepared by a nickel complex induced tetramerization of byclopr~pabenzene.~~~ 206 K. Yamamoto M. Shibutani S. Kuroda E. Ejiri and J. Ojima Tetrahedron Lett. 1986 27 975. 207 J. Ojima E. Ejiri T. Kato S. Kuroda S. Hirooka and M. Shibutani Tetrahedron Lett. 1986,27 2467. 208 J. Ojima K. Yamamoto T. &to and K. Wada Bull. Chem Soc J~R,1986,59,2209. *09 R. Mynott R. Neidlein H. Schwager and G. Wilke Angew. Chem Inr. an. EngL 1986,25 367.