4 Reaction Mechanisms Part (ii) Polar Reactions By J. M. PERCY Department of Chemistry Keele University Keele Staffordshire ST5 5BG 1 Introduction The 1991 literature contained an interesting spread of review articles covering many aspects of physical organic chemistry. One of the subject's cornerstones the Hammett equation forms the subject of two articles with different emphases. One' contains an appraisal of the various substituent constants including field and resonance parameters and a large compilation of data including 530 0-constants and 223 values for up+and up-while the second article2 concentrates on applications. Aspects of carbocation chemistry covered include electronegatively-substituted(or electron deficient) carbocations3 and recent theoretical NMR isotope effect and rearrange- ment st~dies.~ Kochi' has reviewed his work on charge transfer interactions and their importance in organic reactions with emphasis on aromatic nitrations while Ridd6 has summarized the evidence for free radical pathways in aromatic nitrations in nitric acid.Alkynyl carboxylate phosphate and sulfonate esters undergo hydrolysis to pro- duce mechanistically-interesting species some with enzyme inhibitory properties; Stang' has reviewed his groups work in this area. Medium effects were covered by a number of authors; the transfer of organic reactions to water produces some most interesting results; Breslow* examined the scope of hydrophobic effects on the Diels- Alder reaction and benzoin condensation. Micellar effects on reaction rates were reviewed' as were theoretical approaches to understanding solvent effects." The effect of high pressure on polar reactions has provided much mechanistic insight and forms the subject of an account by Isaacs." On a more general note Epiotis12 has questioned the theoretical justification for 'arrow-pushing' particularly it's description of hyperconjugation and found it C.Hansch A. Leo and R. W. Taft Chem Rev. 1991 91 165. * J. Shorter Stud. Org. Chem. (Amsterdam) 1991 42 77. X. Creary Chem. Rev. 1991,91 1625. M. Saunders and H. A. Jiminez-Hugo Chem. Rev. 1991 91 375. J. K. Kochi Pure Appl. Chem. 1991 63 255. J. H. Ridd Chem SOC.Rev. 1991 20 149. P. J. Stang Acc. Chem. Res. 1991 24 304. R. Breslow Acc. Chem Res.1991 24 159. C. A. Bunton SurSactant Sci. Ser. 1991 38 13. 0. Tapia Theor. Models Chem. Bonding 1991 4 435 N. S. Isaacs Tetrahedron 1991 47 8463. N. D. Epiotis THEOCHEM 1991 75 205. 63 J. M. Percy lacking. However this author suspects that it may be some time before a technique computational or otherwise is developed which can rival our familiar toxophilic approach for user-friendliness speed or predictive power. 2 Solvolysis and Carbocations Very stable carbocations have been described;13tris( 1-azuleny1)methanes [1(a)-(c)] have pKR+ values of 11.3 11.4 and 10.3 respectively in 50% aqueous acetonitrile the highest values for simple hydrocarbon-derived cations. l(a) R = H; (b) R = Me; (c) R = C02Me. Heats of reaction have been determined for five highly-stabilized carbocations with amines in sulfolane using a calorimetric te~hnique.'~ A good correlation between the heat of reaction and pKR+ was reported but pKBH+ (aqueous) was a poor model for amine nucleophili5ty and the measured heat of reaction proved less sensitive than anticipated to steric hindrance in the nucleophile.The flash photolysis technique has afforded rate constants for the reaction of azide anion and 28 stabilized carbo~ations,'~ validating the 'azide clock' method much used as a probe of solvolytic reactions. Mayr's group have used flash photolytic16 and condu~timetric'~ methods to study the reactions of allylsilanes enol ethers and silyl enol ethers with diaryl carbenium ions. The allyl metals can be regarded simply as donor-substituted alkenes which undergo rate-determining addition to diaryl carbenium ions to form &stabilized carbenium ions (Scheme 1).A nucleophilicity scale for carbon nucleophiles covering seven orders of magnitude is included in the second paper. Scheme 1 Gassman and co-workers have describedI8 a series of experiments designed to probe the nature of allyl cations; cycloaddition trapping reactions show that proton- ation of (2a) and deuteriation of (2b) at -78°C produces distinct cations (3a) and (3b) and not the common species (4). At temperatures below -23 "C diene or cation interconversion fails to compete with cycloaddition though this depends on the l3 S. Ito N. Morita and T. Asao Tetrahedron Lett. 1991 32 773.E. M. Arnett and S. Venimadhavan J. Org. Chem. 1991 56 2742. " R. A. McClelland V. M. Kanagasabapathy N. S. Banait and S. Steenken 1. Am. Chem. Soc. 1991 113 1009. 16 J. Bartl S. Steenken and H. Mayr J. Am. Chem. Soc. 1991 113 7710. 17 G. Hagen and H. Mayr J. Am. Chem. Soc. 1991 113 4954. l8 P. G. Gassman D. A. Singleton and H. Kagechika J. Am. Chem. SOC.,1991 113 6271. Reaction Mechanisms -Part (ii) Polar Reactions acid used. Acids with large counter-ions cause cations (3a) and (3b) to interconvert; it is proposed that the allylic cations exist as tight ion pairs in which the counter-ion controls the reactivity. The biologically-important cyclization of squalene to steroid hormones is believed to involve extended .rr-participation; secondary isotope effects on the solvolysis of (5) in highly polar media are produced" as evidence for concerted tricyclization.In superacid media menthol (6) and neomenthyl chloride (7) were expected to form the simple menthyl cation (8); Dean and Whittake8' have shown that they form distinct cations neither via (8) but both involving group migrations in concert with leaving group departure. It was anticipated that the a-hydroxyketone (9) would afford a destabilized a-ketocation (10) on treatment with trifluoromethane sulfonic acid (Scheme 2). However Olah and Wu2' detected the products of a concerted elimination of benzaldehyde instead. If additional groups capable of stabilizing positive charge were present at the a-position products formed from a-keto cations were observed.19 0. Kronja M. Orlovic K. Humski and S. Borcic J. Am. Chem. SOC.,1991 113 2306. 20 C. Dean and D. Whittaker J. Chem. Soc.,Serkin Trans 2. 1991 1541. 21 G. A. Olah and A. Wu J. Org. Chem. 1991 56 2531. J. M. Percy &To +PhCHO / 0 Scheme 2 Amyes and Richard22 have investigated a-azido benzyl cations (1 l) potential intermediates in the Schmidt reaction by which benzaldehydes are converted to benzonitriles by the action of hydrazoic acid. These cations are more stable than (12) their a-methoxy analogues by factors of 16 (lla) and 60 (llb). No Schmidt products were observed in 50% aqueous trifluoroethanol but as the authors point OMe N3 I XJy+ Xd+ ll(a) X =MeO; (b) X =H. 12(a) X =MeO; (b) X =H.out the rate-determining step may be different in the strongly acidic medium used for the preparative reaction with elimination of nitrogen becoming faster than cation hydrolysis. In less stabilized systems the effect of an additional electron withdrawing substituent can be dramatic. R (13) uia C ionization OH 0-7 R Scheme 3 22 T. L. Amyes and J. P.Richard J. Am. Chem. SOC.,1991 113 1867. Reaction Mechanisms -Part (ii) Polar Reactions 67 Diol(l3) and its C1 antipode (14) undergo stereospecific spirocyclization (Scheme 3) via displacement of the primary hydroxyl group when R is meth~xy.~~ Less electron withdrawing substituents at C-2 allow the more usual C-1 ionization mechanism to compete. Nitrous acid deamination of primary amines has been studied using careful stereochemical experiments; the reaction is almost completely stereospecific compelling evidence against primary carbenium ion formation.24 3 Other Nucleophilic Substitutions Of note this year is a rise in the number of publications dealing with reactions at phosphorus presumably reflecting the increasing importance of nucleotide and oligonucleotide chemistry.Lonnberg's group2' have published a number of papers in this area studying compounds that model dinucleotides. Monomethyl- and monoisopropyl esters of adenosine-3'-monophosphate[15(a) and (b)] undergo three parallel reactions in aqueous solution (Scheme 4); group transfer to the 2'-ester (path a),hydrolysis to a mixture of 2'-and 3'-monophosphates (path b) and cleavage of the glycosidic bond (path c) have all been detected.+ HO 0 / P=O P=O 0 OH HO' I HO/I0-""TiAd 0- \ P=O RO/),-15(a) R Me; (b) R = Pr'. HO 0 \ ,P= RO I 0- 0 OH \ P=O HO /),-Scheme 4 For 15(a) all three pathways operate at comparable rates in acid while under neutral conditions (pH 4-9) path a operates independent of pH. Above pH 9 path b becomes dominant. With 15(b) path c becomes faster than path b. Details of the mechanisms at phosphorus are discussed. Similar studies for a range of dinucleotide 23 L. A. Paquette and J. T. Negri J. Am. Chem. SOC.,1991 113 5072. 24 D. Brosch and W. Kirmse J. Org. Chem. 1991 56,907. 25 M. Oivanen R.Schnell W. Ptleiderer and H.Lonnberg J. Org. Chem. 1991 56 3623 J. M. Percy monophosphates (UpU UpA ApU and ApA) expose reactivity differences centred on the acidities of the 2’- and 3’-hydroxyl groups.26 Dinucleotides with a 5’-uridine are more readily hydrolysed at the diester linkage than those with an adenine in this position but the depurination rate is insensitive to the nature of the heterocyclic base. Menger2’ has published a critical discussion of Breslow and Hwang’s study of the hydrolysis of ApA and UpU in which negative rate constants were reported. Phosphonoformate esters ( 16) are potential pro-drugs for the phosphonoformate trianion (17) an antiviral compound for use in AIDS therapy but of extremely low membrane permeability. Hydrolysis studies on triesters reveal a competitive situation between P-C and C-0 cleavage raising a problem in pro-drug design.28 Initial cleavage of the R-0 bond in (16) exposes a carboxylate anion which drives decar- boxylation to the hydrogen phosphonate diester.When the conjugate base of ROH is a good leaving group which it must be for antiviral activity this situation prevails. Only by making the conjugate base of R’OH a better leaving group than the conjugate base of ROH can the pro-drug be successfully channelled through to (17). 0 0 Scheme 5 A mechanism has been proposed for the hydrolysis of phosphonopyruvate (18) which involves pre-equilibrium proton transfer to the carboxyl oxygen followed by P-C bond cleavage and tautomerization (Scheme 5).29 Forbes and Maskill examined the solvolyses of arenesulfonyl chlorides in aqueous triflu~roethanol.~’ A shift in mechanism from an associative to a dissociative pathway as the arene became strongly electron-donating was reported by earlier authors; this was not confirmed by the present study.Halogen-exchange reactions of 5-bromo- and 5-iodocyclopentadiene are faster than in the corresponding cyclopentyl compounds3’ but the data so far obtained do not allow SN2 and sN2’ pathways to be distinguished nor do they rule out SET processes. Banait and Jenck~~~ have shown that cY-D-glUCOpyranOSyl fluoride under- 26 P. Jarvinen M. Oivanen and H. Lonnberg J. Org. Chem. 1991 56 5396. 27 F. M. Menger J. Org. Chem. 1991 56 6251. 28 E. S. Krol J. M. Davis and G. R.J. Thatcher J. Chem. SOC.,Chem. Commun. 1991 118. 29 S. Freeman W. J. Irwin and C. H. Schwalbe J. Chem. SOC.,Perkin Trans 2 1991 263. 30 R. M. Forbes and H. Maskill J. Chem. SOC.,Chem. Commun. 1991 854. 31 R. Breslow and J. W. Canary J. Am. Chem. SOC.,1991 113,3950. 32 N. S. Banait and W. P. Jencks J. Am. Chem. SOC.,1991 113,7951. Reaction Mechanisms -Part (ii) Polar Reactions goes concerted nucleophilic (ANDN) displacement with anionic nucleophiles a reaction pertinent to the mechanism of action of glycosidase enzymes. 4 Elimination Reactions Hall and co-~orkers~~ examined the formation of methacrylamide (19) from (20) in strong acid (90-102% sulfuric acid) using NMR methods. The E2 elimination described by (21) is the rate-determining step.Labelling the oxygen ("0) of the scissile C-0 bond shows retention of the label ruling out pre-equilibrium exchange of oxygen via an El loss of hydrogen sulfate. Deuterium isotope effects identified a rate-limiting proton transfer and considerations of pK support the E 2 mechanism. Amyes and Richard34 uncovered an interesting pericyclic elimination in the course of their studies of changes between mechanistic pathways. Cumyl derivatives (22) undergo solvolysis the mechanism being determined by substituent X; when X is more electron-withdrawing than a meta-fluorine (ax+> 0.34) unexpectedly large (up to 30%) amounts of a-methylstyrene are detected. These products are formed by pericyclic Ei or (cyclo-D,D,AN) eliminations and are enforced by the instability of intermediates on the stepwise solvolysis pathway.m Eliminations across C-S bonds to form sulfines occur when (23) is treated with methoxide in methanol via a mechanism at the (E lcB)J( E lcB)irrevb~rderline.~' The elimination is facile and possibly facilitated by repulsion between the dipoles of the sulfoxy and sulfonyl groups. 33 C. D. Hall C. J. Leeding S. Jones S. Case-Green I. Sanderson and M. van Hoorn J. Chem. SOC. Perkin Trans. 2 1991 417. 34 T. L. Amyes and J. P. Richard J. Am. Chem. SOC.,1981 113 8960. 35 J. L. Kice and L. Kupczyk-Subotkowska J. Org. Chem. 1991 56 1424. J. M. Percy Sulfene intermediates are involved36 in the reactions of methoxide with aryl mesylates (24); pyrrolidine imine (25) was used to trap these sulfonyl analogues of ketene as sulfone (26).This pathway only predominates when the aryl group is 4-nitrophenyl; less electron-withdrawing groups favour reaction at sulfur. Reactions forming imines3’ from (27) were described; eliminations are regio- specific leading to benzylidenes (28). Base-promoted and solvolytic pathways were identified the former occurring via an E2 mechanism while the latter involves initial leaving-group departure to form a nitrenium contact ion pair from which rate-limiting proton transfer occurs. ~ R PhCN~ + ArO-Scheme 6 The Korean group has also probed the reactions of (E)-0-arylbenzaldoximes (29) with secondary amine~;~~ E2 and S,Ar (Scheme 6) mechanisms compete when the aromatic moiety is highly activated.Highly concentrated or ’strong bases and the picryl leaving-group favour the latter pathway. 5 Addition Reactions The trifluoroacetylation of aryl vinyl sulfides (30) has been in~estigated;~~ second-order rate constants for five para-substituted compounds can be fitted to the Hammett equation with p = -3.0. Deuterium isotope effects at the P-carbon (kH/ kD = 2.5) were consistent with a stepwise trifluoroacetylation via a carbenium ion but at variance with the result of a stereochemical experiment. The introduction of 36 M. J. Pregel and E. Buncel .I.Chem. SOC.,Perkin Trans 2 1991 307. 37 B. R. Cho and S. Y. Pyun J. Am. Chem. SOC.,1991 113 3920. 38 B. R. Cho B. K. Min C. W. Lee and J. T. Je J. Org. Chem. 1991,56 5513. 39 M.Hojo R. Masuda Y. Kamitori and E. Okada 1Org. Chem. 1991,56 1975. Reaction Mechanisms -Part (ii) Polar Reactions 71 deuterium at the P-carbon in a defined stereochemical relationship to the arylthio- group led to the recovery of trifluoroacetylated product in which the stereochemistry was completely retained. The authors propose a mechanism in which addition of the electrophile and proton-loss are concerted. Kresge and Yin4’ have investigated the hydrolysis of 1-methoxycyclooctene (31); by analogy with 1-methylcyclooctene it was anticipated that protonation would be reversible. This has been attributed to some unusual conformational feature of the eight-membered ring but it was shown that the hydrolysis follows the well-established general acid catalysis mechanism.A key piece of evidence is the authors’ failure to recover deuterated starting material after incubation in perdeuterophosphate buffer at pH 8 after the reaction had proceeded to 50% completion. Idtramolecular catalysis of vinyl ether hydrolysis has been identified41 with an effective molarity of 290 M. The carboxyl group of (32) is the most efficient intramolecular catalyst of a reaction involving proton transfer to carbon though the origin of this catalytic effect is unclear. The epoxidation of alkenes is an important synthetic reaction to which Beak and Woods have applied the endocyclic restriction test.42 By making the epoxidation intramolecular either transition state (33) or (34) (Scheme 7) can be preferred by adjusting the tether length.With the short tether (n = l) labelling studies showed that an intermolecular reaction occurred but when the longer tether was present the reaction was exclusively intramolecular supporting Bartlett’s ‘butterfly’ mechan- ism (34). 0 \ clh-+ 02*H -C1YYC02*H II I II I n=lor9 Scheme 7 OH Adamantylidene adamantane bromonium ion (35) has been isolated43 and used to prepare the perdeutero- trans-2-bromo-1-cyclohexyltriflate (36) in unusually high yield. Degenerate bromine transfer from (35) to adamantylidene adamantane occurs with a calculated second-order rate constant of 2 x lo7 M-’ s-’ suggesting to these authors that intermolecular Br+ transfer from bromonium ions to alkenes could be a kinetically-significant process during alkene bromination.The Paris groupa have 40 A. J. Kresge and Y. Yin Can. J. Chem. 1991,69,84. 41 A. J. Kirby and N. H. Williams J. Chem. Soc. Chem. Commun. 1991 1643. 42 K. W. Woods and P. Beak J. Am. Chem. Soc. 1991,113 6281. 43 A. J. Bennet R. S. Brown R. E. D. McClung M. Klobukowski G. M. Aarts B. D. Santarsiero G. Bulluci and R. Bianchini J. Am. Chern. Soc. 1991,113 8523. 44 M.-F. Ruasse S. Motallebi and B. Galland J. Am. Chem. Soc. 1991,113 3440. J. M. Percy examined the role of solvents in alkene bromination using solvent isotope effects and Grunwald- Winstein parameters. In protic media solvent assistance to cleavage of the inter-bromine bond is provided whereas in halogenated solvent this role is fulfilled by a second molecule of bromine which aids progress from charge transfer complex to bromonium and tribromide ions in a reversible process.Bromonium ions can be trapped by solvent when bromination reactions are performed in damp acetonitrile leading to a range of products; this year saw the publication of a kinetic and product distribution ~tudy.4~ 6 Aromatic Addition and Substitution A number of interesting results have been described in the area of electrophilic aromatic substitution. Second-order rate constants have been measured for nitration reactions in concentrated aqueous triflic acid allowing medium effects to be assessed.46 The NO2+ rates show minimal dependence on the acidity or nature of the medium (though these factors do affect the active concentration of the nitrating species).The nitration of methylphenyl sulfone shows biphasic behaviour passing through a maximum at 92% (w/v) triflic acid. The decreasing activity of water as the percentage of triflic acid rises results in increasingly strong interactions between ionic species. This begins to lower the concentration of NO2+ and depress the rate. Nitrations in dinitrogen pentoxide and using nitronium salts have been examined using "N CIDNP NMR. In the former medium SET processes are clearly visible,47 particularly in the nitrodecarboxylation of 3-nitrobenzoic acid and are implicated in its nitration to 3,5-dinitrobenzoic acid. The nitrosation of phenol by isopentyl nitrite (IPN) and S-nitroso-aminopenicillic (SNAP) acid has been st~died.~' The two electrophiles react by different mechanisms; the former electrophile (IPN) undergoes prior hydrolysis to nitrous acid which nitrosates via a polar mechanism whereas SNAP homolyses and nitrosates via a free radical pathway.Friedel-Crafts acetylation of naphthalene affords mixtures of 1-and 2-acetonaph- th~ne;~~ different rate laws were obtained for formation of the two products the a-adduct being formed via a third-order reaction with a second-order process affording the P-isomer. Steric effects at the cr-complex level are responsible for the difference in pathways; the effects exert themselves in the transition state for proton 45 G. Belluci R. Bianchini and C. Chiappe J. Org. Chem. 1991 56 3067. 46 N. C. Marziano C. Tortato and M. Sampoli J.Chem. SOC.,Perkin Trans. 2 1991 645. 47 R. B. Moodie A. J. Sanderson and R. Willmer J. Chern. Soc. Perkin Trans 2 1991 645. 48 S. M. N. Y. F. Oh and D. L. H. Williams J. Chem. SOC.,Perkin Trans. 2 1991. 685. 49 D. Dowdy P. H. Gore and D. N. Waters J. Chem. SOC.,Perkin Trans. 2 1991 1149. Reaction Mechanisms -Part (ii) Polar Reactions 73 loss and rearomatization the more hindered a-species requiring a second molecule of aluminium trichloride to prepare the Wheland intermediate for proton loss. Galli has compared four methods for aromatic iodination5' by competition experi- ments between durene and mesitylene. Within 2 or 3% the mesitylene/durene rate ratio of 50 1 remains constant for the four methods which differ considerably in reactivity.Galli concludes that the reactive species in all four methods is the iodonium ion I+. The basicity of alkali metal alkoxides in methanol forms the subject of a number of papers two of which deal with the reversal of the normal order of basicity as the alkali metal counter-ion is varied. Highly activated anisole derivatives which can form 1:2 and 1 :3 adducts with methoxide in methanol are more reactive with sodium methoxide than with potassium. These higher adducts involve highly local- ized charge which is more effectively solvated by the smaller sodium cation.51 The excess basicity method (X function) has been used to study the reactions of eleven less-activated arene~;'~ m* depends on the degree of solvation in the transition states leading to the Mesenheimer complexes and explain the higher reactivity of ortho- chloronitrobenzene than the para-isomer in concentrated (>3M) methoxide sol- utions.The reactions of the former substrate exhibit a higher slope parameter consistent with a lower degree of external solvation. Transition state (37) is proposed CliTY";[I ' 0- / to explain this difference. With carbon nucleophiles Crampton and Stevens have shown strong parallels between structure and reactivity in the a-adduct forming reactions of carbon nucleophiles with activated anisoles and in their protonation behaviour suggesting that the timing of electronic and solvent reorganization events is similar in both processes.53 The addition of vinyl Grignard reagents to nitroarenes forms the subject of a rigorous product distribution studys4 and a general procedure for fluorodenitration of aromatic compounds was also published including some reactivity data.s5 7 Proton Transfer and Carbanions Aspects of this area studied this year range from the most fundamental proton transfer processes to carbanionic rearrangements of synthetic utility.Berg and JencksS6 have used NMR methods to study the dissociation of ammonium-ion-water complexes. Rate constants for hydrogen bond breaking 50 C. Galli J. Org. Chem. 1991 56 3238. 51 P. C. M. F. Castilho M. R. Crampton and J. Yarwood J. Chem. SOC.,Perkin Trans. 2 1991 639. 52 A. Bagno G. Scorrano and F. Terrier J. Chem. SOC.,Perkin Trans. 2 1991 651. 53 M. R. Crampton and J. A. Stevens J. Chem.SOC.,Perkin Trans. 2 1991 1715. 54 M. Bosco R.Dalpozzo G. Bartoli G. Palmieri and M. Petrin J. Chem. SOC.,Perkin Trans. 2 1991 657. 55 M. Maggini M. Passudetti G. Gonzales-Trueba M. Prato U. Quintilly and G. Scorrano J. Org. Chem. 1991 56 6407. 56 U. Berg and W. P. Jencks J. Am. Chem. SOC.,1991 113 6997. J. M. Percy between 3-substituted quinuclidines and water show a dependence on base strength with /3 = -0.25. Various contributions to the free energy of hydrogen bond breaking were analysed including dispersion forces between donor and acceptor and the energy required to create a cavity for the unbound water molecule to diffuse into. The results suggest that an earlier analysis of negative PN values for phosphoryl transfer reactions based on nucleophile desolvation was correctly made.The enoliz- ation of carbonyl compounds is of fundamental importance and is much studied though usually in the reverse (ketonization) dire~tion.’~ A direct study of aldehyde enolization in concentrated acetate buffer solutions revealed concerted catalysis of the enolization reaction by both acetate and acetic acid components of the buffer. The concerted process is most significant when both acid and base catalysis is effective and appears to be more important for aldehydes than ketones. This difference in behaviour is attributed to the lower basicity higher enol content and higher C-H acidity of the aldehydes compared with the ketones. The high rates of proton abstraction achieved by enzymes from carbon acids such as carbonyl deriva- tives forms the subject of a recent This probes the role of electrophilic catalysis and argues that it’s effect is to lower the pKa of the a-protons to values comparable with those of the active site bases facilitating the rapid proton transfers required.The effect of carbonyl protonation on a-proton acidity is used to model the electrophilic effect. The kinetic acidity of cubane has been determined” using a 3H NMR method; the cage hydrocarbon is shown to be 6.6 x times less acidic than benzene approximately five times more acidic than expected from ‘H-13C coupling constants. Cubane is less acidic than cyclopropane consistent with the lower s-character of its C-H bonds. Equilibrium acidities measured in DMSO have been used to estimate aromatic stabilization energies in heterocyclic anions.60 A typical procedure involves the comparison of a cyclic species {(38) pKa = 13.5) with an acyclic model {(39) pKa = 18.7); the difference is converted to an aromatic stabilization energy and attributed to the formation of a (4n + 2) electron anion.The electroreduction of a-bromoamides in DMF has been used6* to establish a pKa scale in DMF covering 10 orders of magnitude for weak acids and related to the DMSO acidity scale; this allows the calculation of pKas in DMF given values in the other solvent. An extended caesium ion pair acidity scale in THF has been reported62 and used to study the acidity of oxime (40),an interesting class of enolate equivalents The oxime 57 A.F. Hegarty and J. Dowling J. Chem. Soc Chem. Commun. 1991 996. 58 J. A. Gerlt J. W. Kozarich G. L. Kenyon and P. G. Gassman J. Am Chem. Soc. 1991 113 9667. 59 R. E. Dixon A. Streitweiser P. G. Williams and P. E. Eaton J. Am. Chem. Soc. 1991 113 357. 60 F. G. Bordwell and H. E. Fried J. Org. Chem. 1991,56 4218. 61 F. Maran D. Celadon M. G. Severin and E. Vianello J. Am Chem. Soc. 1991 113 9320. 62 A. Streitweiser J. C. Ciula J. A. Kron and G. Thiele J. Org. Chem. 1991 56 1074. 63 J. C. Ciula and A. Streitweiser J. Org. Chem. 1991 56 1989. Reaction Mechanisms -Part (ii) Polar Reactions ethers are around 10" times less acidic than the corresponding ketones due to the lower anion stabilizing ability of the nitrogen atom in the former species.Arnett and Mae@ have investigated the thermochemical properties of a range of syntheti- cally important organolithium bases including the 'superbases' formed by the addition of a metal t-butoxide to the organolithium species. The superbase lithium hexamethyldisilazide/potassium t-butoxide (LiHMDS/ Bu'OK) is intermediate in reactivity between LiHMDS and KHMDS but identical with KHMDS/Bu'OLi when heats of deprotonation of iso-propyl alcohol are measured suggesting that the same active species is present. Reactions involving carbanions include an interesting intramolecular addition to an unactivated C=C bond (Scheme 8);65the reaction is totally regiospecific and more stereospecific than comparable radical mediated processes. Calculations at the 3-21G level support a chair transition state for this process.A related process involves intramolecular attack on an enol ether C=C bond leading to homoallylic alcohols in preference to metallation at the a-position.66 c-,-LLi -dLi Scheme 8 Bowden's group at Essex6' have studied the E-to 2-isomerization in substituted chalcones as models for biologically active compounds. Isomerization occurs uia rate determining attack by amines or methoxide at the P-carbon; Hammett and H,-correlations are reported. 8 Carbonyl Derivatives Enols continue to attract attention with the publication of a homogeneous catalytic method for their generation from allylic alcohols6* and a study of structural effects on the stability of enols derived from cyclic benzyl ketones (41).69Ketone (pKaK) and enol (pKaE) acidity both decrease with increasing ring size; the effect of the phenyl group is to increase the enol content by a factor of 103-104over non-benzylic ketones.A naturally-occurring dienol (42) involved in bacterial catechol metabol- 41(a) n = 1; (b) n = 2; (c) n = 3. 64 E. M. Arnett and K. D. Moe J. Am. Chem. Soc. 1991 113 7068. 65 W. F. Bailey A. D. Kharolkar K. Gavaskar T. V. Ovska K. Rossi Y. Thiel and K. B. Wiberg J. Am. Chem. Soc. 1991 113 5720. 66 W. F. Bailey and L. M. J. Zarcone Tetrahedron Lett. 1991 32 4425. 67 K. Bowden C. K. Duah and R. J. Ranson J. Chem. Soc. Perkin Trans. 2. 1991 109. S. H. Bergens and B. Bosnich J. Am. Chem. Soc. 1991 113,958. 69 S. Eldin R. M. Pollack and D. L. Whalen J.Am. Chem. Soc. 1991 113 1344. J. M. Percy co; co; co; I I I ism has been shown to exhibit high ~tability.~’ Ketonization occurs via rapid conversion to (43) followed by a slower isomerization to (44). Cyclic hemiacetals exist in equilibrium with open-chain forms (Scheme 9).71 Electron-donating substituents R favour the open-chain form; general base catalysis of hemiacetal breakdown (/3 = 0.60)was detected but acid catalysis is inhibited by the presence of the positively-charged nitrogen. Ring-opening was subject to weak hydronium ion catalysis but general acid catalysis could not be detected. Coleman Scheme 9 and Murray72 have described a detailed analysis of acetaldehyde hemiacetal break- down which is subject to general base catalysis.Consideration of a number of kinetic parameters leads to the conclusion that proton transfer and heavy atom reorganiz- ation are coupled. A number of other models for proton transfer catalysis are discussed and the mechanistic criteria used to support and assign these mechanisms is appraised. Orthoester hydrolysis provided the subject of a number of classic early physical organic investigations; Capon and Lee73 have revisited the area with the relatively unexplored orthoesters of D-glucose and D-mannose. They present some evidence for hemiorthoester intermediates in the hydrolyses of these complex species.. A synthetic catalyst for hemiacetal breakdown has been reported74 which achieves modest rate accelerations for the mutarotation of tetramethylglucopyranose and the dissociation of glycolaldehyde dimer.G~thrie’~ has applied Marcus theory to the question of concertedness in acyl transfer reactions which was raised in last year’s Report. He concludes that ‘in essentially all the reactions of aryl acetates the reactions have no intermediates of significant lifetimes because of the very small intrinsic barriers for making or breaking a bond to an aryloxide anion.’ He predicts 70 C. P. Whitman B. A. Aird W. R. Gillespie and W. J. Stolowich J. Am. Chem. SOC.,1991 113 3154. 71 P. E. Sdrensen R. A. McClelland and R. D. Gandour Acta Chem. Scand. 1991,45 558. 72 C. A. Coleman and C. J. Murray J. Am. Chem. SOC. 1991 113 1677. 73 9. Capon and Y. Lee J. Org. Chem. 1991 56,4428. 74 C. Gennari F.Molinari M. Bartoletti U. Piarulli and D. Potenza J. Org. Chem. 1991 56 3201. 75 J. P. Guthrie J. Am. Chem. Soc. 1991 113 3941. 77 Reaction Mechanisms -Part (ii) Polar Reactions concerted reactions for alkoxyl leaving groups/nucleophiles with pK I10 and a transition to a stepwise mechanism for leaving groups in the pK range 11-12. The intrinsic barrier for hydroxyl attack at the carbonyl group is high due to significant solvation changes that occur around this special nucleophile during the addition. Nucleophilic attack at the neutral carboxyl is not generally considered to be an important pathway in the reaction of carboxylic acids with organometallic reagents. It has been claimed76that this direct nucleophilic attack occurs in competition with deprotonation when benzoic acid is treated with butyllithium.The argument rests on the formation of significant amounts of tertiary alcohol (46) in the early stages of the reaction; the alcohol must be formed by organometallic attack on ketone (45) present in the reaction mixture. However as (46) cannot be formed from the dianionic intermediate by loss of lithium oxide it is argued that the ketone results from the less stable intermediate (47) formed by direct organometallic attack on the neutral carboxyl. SET mechanisms have not been ruled out for any of these processes. Ph Bu Bu Ph Bu OLi phKBu Y Y Br(CH,),,CO,-+NBu, 0 OH OH One reagent of choice for macrolactonization of a,w-bromoacids is caesium carbonate; claims have been made that the caesium ion acts to preorganize the nucleophilic and electrophilic centres in a cyclic precursor thus promoting macro-cyclization ( kin,,,) and supressing polymerization ( kint,,).This hypothesis is dis-missed77and shown to be an artefact; the effect of added salts on the formation of ll-undecanolide from (48) was studied and shown to affect the yield of lactone considerably. However the low yield for added lithium salts results because both kinterand kin,, were reduced by tight ion-pairing between the carboxylate nucleophile and the lithium counter-ion. Extending the reaction time with the lithium salts allowed comparable (to the caesium case) yields of lactone to be isolated. Lactone hydrolysis by the unusual A,,2 mechanism was reported by Moore and S~hwab~~ during attempts to selectively cleave the amido-function of (49).Epimerization occurred at C4 only while a '80-labelling experiment showed oxygen exchange at both positions in the lactone. Exchange of the carbonyl oxygen is explicable by the AA,2 mechanism but only the unusual A,,2 pathway via (50) explains exchange into the ring position and the epimerization at C4.Lactone reduction and hydrolysis COH2 PhCONH 0 OH+ Hf$: JY PhCONH Ga 76 C. Einhorn J. Einhorn and J.-L. Luche Tetrahedron Lett. 1991 32 2771. 77 C. Galli and L. Mandolini J. Org. Chem. 1991 56 3045. 78 J. A. Moore and J. M. Schwab Tetrahedron Lett. 1991 32 2331. J. M. Percy has been studied using thermochemical and theoretical methods,79 affording a data set which allows evaluation of the MM3 program when applied to these important cyclic species.Two interesting papers deal with aspects of ketene chemistry; an alkynyl phosphate triester (51) is converted to ketene (52) by the action of a bacterial phos-photriesterase" which is rapidly inhibited by this reactive intermediate. Trimethyl- silyl ketene (53) undergoes neutral hydrolysis (kH20) in aqueous acetonitrile unusually slowly;81 (52) is 390-times more reactive than (53). This is attributed to a ground state stabilizing effect exerted by the silicon; however the TMS group accelerates the acid and base-catalysed hydrolyses by stabilizing negative charge at the a-position in (54) in the base-catalysed pathway and positive charge at the P-position in (55) the intermediate in the acid-catalysed reaction.The hydrolysis /=c=o Bu-OP(O)(OEt)2 R (52) R = Bu; (53) R = Me,% (54) (55) of aryl isocyanides in aqueous DMSO has been characterized8* using a basicity function and Hammett correlations. Stepwise (at high basicity) and concerted (at lower basicity) mechanisms have been proposed while support is provided for the dipolar representation (56) of the isocyanide group rather than the carbene form (57) in polar media. 9 Other Reactions Kre~ge~~ has revisited the hydrolysis of nitramide (58) which affords water and nitrous oxide. A stepwise decomposition reaction was proposed based on general base catalysis of the hydrolysis with Eigen curvature and on isotope effects. A second studys4 reveals that the monoanions of gem-diols (59) are unusually effective catalysts for the decomposition and a proposal is made that these compounds act as bifunctional catalysts uia transition state (60).This mode of catalysis avoids 79 K. B. Wiberg and R. F. Waldron J. Am. Chem. Soc. 1991 113 7697. 80 J. N. Blankenship H. Abu-Soud W. A. Francisco F. M. Raushel D. R,Fischer and P. J. Stang J. Am. Chem. Soc. 1991 113 8560. 81 A. D. Allen and T. T. Tidwell Tetrahedron Lett. 1991 32 7697. 82 I. D. Cunningham G. J. Buist and S. R. Arkle J. Chem. SOC.,Perkin Trans. 2 1991 589. 83 C. H. Arrowsmith A. Awwal B. A. Euser A. J. Kresge P. P. T. Lau D. P. Onwood Y. C. Tang and E. C. Young J. Am. Chem. SOC.,1991 113 172. 84 C. H. Arrowsmith A.J. Kresge and Y. C. Tang J. Am. Chem. Soc. 1991 113 179. Reaction Mechanisms -Part (ii) Polar Reactions NH,NO 0-(58) (59) expulsion of the highly unstable oxide anion (02-). Hegarty's group studied a related which involves the hydrolysis of nitrolic acids to nitrile oxides (Scheme 10). The rate of reaction depends on the stereoelectronic relationship between the nitro-leaving group and the lone pair on the oximato-nitrogen. The 2-isomers which contain an antiperiplanar relationship are more reactive by an unspecified factor. '\i'""" -R-ZF&-O-+ HNOz O2N Scheme 10 Guthrie has applied Marcus theory to the aldol condensations6 using the large set of pK data for enols and enolates currently available. Intrinsic barriers were calculated for both addition and elimination steps; this should allow the calculation of rate constants for novel aldol reactions.Solvent counter-ion and isotope effects have been used to probe the transition state of the important and highly useful oxy-Cope rearrangement (Scheme 1l).87 Scheme 11 11 Isotope effects reveal a minimal degree of bond-making between the C1 and C6 allylic termini while dissociation of the C,-C bond is extensive. The reaction is much faster in DMSO and the possible role of aggregation is discussed. The Nef reaction involves a highly-useful conversion of a nitroalkane to the corresponding ketone and shows an interesting y-silicon effect. Hwu and Gilbert" have shown that a suitably-positioned y-trimethylsilyl group facilitates this reaction.Whereas (61a) readily undergoes Nef degradation to (62) upon treatment with 61(a) R = Me&; (b) R = CH,OMe (62) 85 C. Egan M. Clery A. F. Hegarty and A. J. Welch 1. Chem. SOC.,Perkin Trans. 2 1991 249. 86 J. P. Guthrie J. Am. Chem. Soc. 1991 113 7249. 87 J. J. Gajewski and K. R. Gee J. Am. Chem. SOC.,1991 113 967. 88 J. R. Hwu and B. A. Gilbert J. Am. Chem. Soc. 1991 113 5917. J. M. Percy KH/THF followed by dilute acid (61b) resists this treatment. The manifestation of this effect is attributed to the presence of a carbocation on the reaction pathway. 10 Probes of Polar Reactions Isotope leaving group and solvent effects were all well represented in the 1991 literature. Solvent nucleophilicity (Y)scales were used89 to support a competing- pathway view of the sulfonyl chloride (63).A correlation of the solvolysis rate with Y, is curved or broken and the product selectivity varies with solvent composition. The findings are thought to be inconsistent with a variable transition state model for the reaction. A new improved solvent nucleophilicity scale NT has been proposed,” based on solvolysis of (64). The model compound is easy to prepare and reacts with the more nucleophilic solvents at convenient rates at ambient temperature. Me CF3SOS RZ R R’ Me0 (65) (66) R = isoprenoid Specific solvent interactions form the subject of a number of publications. In the hydrolysis of acyl triazoles (65) the steric effects exerted by R’ and R2are solvent dependent.” This result indicates that steric substituent constants for alkyl and other hydrophobic groups contain a substantial solvation-related contribution.Headley9* examined the solvent dependent variation in order of basicity in the series ammonia to trimethylamine. Using potentiometric titration and multiple parameter regression methods a series of solvent attenuation factors (SAF‘s) were calculated which allow the transfer of gas phase basicities to solution. Specific solvation differences between alkyl and aryl groups were identified;93 incorporating these differences in Grunwald- Winstein treatments leads to improved correlations via a reduction in dispersion (the tendency of different binary mixtures to form separate correlations). The kBr/kcl element effect is often used to distinguish between mechanisms in substitution reactions at aryl vinyl and acyl carbon with kBr/kcl > 1indicating rate-determining cleavage of the carbon-halogen bond.A theoretical study casts doubt on this simple inter~retation~~ which fails to take account of factors such as differential ground 89 I. S. Koo T. W. Bentley D. H. Kang and I. Lee J. Chem. Soc. Perkin Trans. 2 1991 175. 90 D. N. Kevill and S. W. Anderson J. Org. Chem. 1991 56 1845. 91 W. Blokzijl M. J. Blandamer and J. B. F. N. Engberts J. Org. Chem. 1991 56 1832. 92 A. D. Headley J. Org. Chem. 1991 56 3688. 93 T. W. Bentley I. S. Koo and S. J. Norman J. Org. Gem 1991 56 1604. 94 S. Hoz,H. Basch J. L. Wolk Z. Rappoport and M. Goldberg J. Org. Chem.1991 56 5424. Reaction Mechanisms -Part (ii) Polar Reactions state stabilization. Other leaving group ratios (mesylatelpara-nitrobenzoate and tosylatelpara-nitrobenzoate) were shown to be relatively insensitive to the effects of temperature and structure for a reasonable range of corn pound^.^^ These ratios offer potentially useful links to be made between various sets of published data. Isotope effects have been used to characterize the transition states for phos- phodiester hydrolysisy6 quaternization reaction^:^ and nucleophilic displacements In by thi~phenoxide.~~ a study of aniline acylation a ''N effect was used to distinguish between stepwise and concerted acyl transfer pathways.99 Xie and Saundersloo have examined the temperature variation in primary kH/kD effects for enolate formation from labelled 2-pentanone by lithium amide bases.Some unusually large primary isotope effects and an isotope effect on enolate geometry suggest a complex mechanism for deprotonation with more than one active basic species. Poulter and Mantz"' suggest that the phosphorothioate leaving group in (66) may prove a useful probe of reactions where ion-pair return is implicated particularly in reactions at enzyme active sites. This leaving group contains a highly nucleophilic sulfur atom and an added incentive to carbon-sulfur bond formation in the strong phosphorus-oxygen double bond. 95 T. W. Bentley M. Christl and S. J. Norman J. Org. Chem. 1991 56 6238. 96 A. C. Hengge and W. W. Cleland J. Am.Chem. Soc. 1991 113 5835. 97 P. Paneth and M. H. O'Leary J. Am. Chem. Soc. 1991 113 1691. 98 Y-R. Fang and K. C. Westaway Can. J. Chem. 1991. 69 1017. 99 Z. J. Kaminski P. Paneth and M. H. O'Leary J. Org. Chem. 1991 56 5716. 100 L. Xie and W. H. Saunders Jr. J. Am. Chem. Soc. 1991 113 3123. 101 C. D. Poulter and D. S. Mantz J. Am. Chem. Soc. 1991 113 4895.