3. (Part i) REACTION MECHANISMS By B.C. Challis (Department of Organic Chemistry Imperial College of Science London S. W.7) Deuterium Isotope Effects.-These are conveniently discussed under three sub-headings primary effects arising from reactions where the isotopically substituted bond undergoes fission ;secondary effects associated with isotopic substitution of bonds not undergoing rupture in the transition state; and solvent effects arising from differences between ordinary water and deuterium oxide as reaction media. Attention is drawn to significant developments in the interpretation of variable isotope effects and these are discussed under both primary and solvent isotope sub-headings in relation to the transition state configuration of proton-transfer reactions.Primary isotope effects. These manifest themselves as a lower rate of deuterium transfer compared to hydrogen (k,lk > 1) and arise from differ- ences between the zero-point vibrational energies of H and D in the ground and transition states. The differences can be calculated for the ground state but not for the transition state where the speculative nature of the vibrations involved evokes considerable enquiry from both theoretical and experimental standpoints. It may be recalled that Westheimer' was the first to suggest from con- sideration of a simple three-centre model that mass-dependent zero-point energy may arise from the unsymmetrical stretching mode (1) in the transition state This led to the prediction in accord with recent experimental findings t+ 4-+ 3 A -H + B + [A---H ---B] (1) that k,/k will pass through a maximum value when the transition state is symmetrical.Westheimer's calculations have been criticised by Bell,2 in particular for failing to take account of bending vibrations and proton tunnelling and this criticism can be justified in at least two recent examples where the experimental isotope effects exceed the calculated energy difference for the loss of stretching vibrations only.3* Thus suggestions have been made that k,/k may in fact be virtually independent of the transition-state or even be at a minimum for the symmetrical configuration.6 F. H. Westheimer Chem. Rev. 1961,61,265. R. P. Bell Discuss. Faraday SOC.,1965,39 16. R.P. Bell and D.P. Onwood J. Chem. Soc.(B),1967,150. 'J. R. Jones R. E. Marks and S. C. Subba Rao Trans. Faraday SOC. 1967,63 111. ' A. V.Willi and M. Wolfsberg Chem. and Ind. 1964,2097. R. F. Bader Canad. J. Chem. 1964,42. 1822. D* 100 B. C.Challis Alber~,~ however has now considered the three-centre transition-state model for proton transfer in more detail and calculated kH/kDfor all possible values of the force constants; it is evident that this model can account for the experimental observations provided no preconceptions are held about the shape of the potential barrier. Also some of these criticisms have been answered by the interesting calculations of More O’Ferrall and Kouba’ employing four- and five-centre transition-state models “(2)and (3) respectively] to account for A-B-H + C + [A-B.***H*...CI # (2) A-B-H + C-D -+ [A-B ..-.H.....C-D]# (3) contributions from bending vibrations and from proton tunnelling. Three important predictions emerge from these calculations Firstly. for proton transferfrom carbon or an ammonium ion to a polvatomic base (MeO- MeS- CN- etc.) kH/kD values pass through a maximum for the symmetrical tran- sition state and are not therefore fundamentally different from those based on stretching vibrations alone. This is illustrated for MeO- in Table 1 where x is the degree of proton transfer. Secondly for proton transferfrom carbon to a monatomic base (e.g. Br- in Table 1 the inclusion of bending vibrations broadens the k,/kD maximum with large isotope effects predicted for product- like transition states.Thirdly the maximum value of kH/kD for proton transfer to carbon is considerably reduced when allowance is made for bending vibrations as illustrated in Table 2 The differences in the predicted isotope effects for the two models are large enough to be detected experimentally and these results must be awaited with interest. TABLE1 Calculated isotope effects from ref. 8 for proton transfer to MeO-and Br- X MeO- Br- 1 1.0 kH/kD 1.0 kH/kD 0-875 3-3 2.8 0.75 5.2 3.8 0.625 7.1 5.5 0-5 7.2 7.3 0-375 5.6 8.3 0.25 4-1 7.8 0.125 3.3 7.2 0 1.1 3-2 W.J. Albery Trans. Farads!) Soc. 1967,63,200. R. A. More O’Ferrall and J Kouba. J. Chm. Soc. (B) 1967,985. Reaction Mechanisms TABLE 2 Maximum isotope effects from ref.8 for proton transfer to curbon Proton Bending and Stretching donator stretching vibrations vibrations only (R,H)C-H 7-0 kH/kD 7.2 kdkD R,Nf-H 6.6 6.6 NEC-H 7.0 10.2 RO-H 7.0 10.2 RS-H 3.0 5.8 F-H 6.8 14.9 CI-H 3.0 7.2 Br-H 2.7 5.9 I-H 2.4 5.8 Until recently the only firm evidence for the incidence of variable primary isotope effects came from studies of pseudo-acid ionization (reported last year)' and from the compilation of Kresge" for aromatic hydrogen exchange reactions. Now Long and his co-workers" report that k,/k ratios for hydrogen exchange in substituted azulenes range from 6 to 9.6. These results which may require slight modification to account for secondary isotope effects,' were obtained by varying the base strength of either the catalysing acid or the substrate.They clearly indicate a maximum isotope effect for the symmetrical transition state and virtually parallel the earlier datag for pseudo-acid ionization Less definitive support comes from other reports of substrate-dependent primary isotope effects in the bromination of acetophenones,4*' for aromatic hydrogen exchange in NN-dimethylanilines l4 and from Kresge and Chiang's l2 detailed kinetic analysis of aromatic hydrogen exchange in trimethoxybenzene. Variable isotope effects for proton transfer from trimethyl- ammonium ions15 and in the mass spectral McLafferty rearrangement l6 have also been rationalised in terms of changes in transition-state symmetry. By and large however the limited data available at present gives no clear indication as to the most satisfactory theoretical representation In fact the choice of an experimental system to test the various theories may be limited to those with uncongested transition states.This is evident from kinetic studies of the iodination of azulene for which proton-loss from the transition state is rate-controlling. The experimental k,/kD ratios are almost independent of the strength of the catalysing base It 15 believed that steric B. C. Challis Ann. Reports 1966,63 278. Soc. 1967 63 200. lo A. J. Kresge Pure Appl. Chem. 1964,8 517. '' J. L. Longridge and F. A. Long J. Amer. Chem. SOC. 1967 89 1287; L. C. Gruen and F. A. Long ibid.,p. 1292. See A. J. Kresge and Y.Chiang J. Amer. Chem. SOC.,1967,89,4411. l3 J. R. Jones R. E. Marks and S. C. Subba Rao Trans. Faraday SOC. 1967,63,933. l4 A. C. Ling and F. H. Kendall. J. Chem. SOC.(B),1967.445. R. J. Day and C. N. Reilley J. Phys Chem. 1967,71 1588 '' J. K. McCleod and C. Djerassi J. Amer. Chem. SOC. 1967,89,5182. 102 B. C.Challis effects arising from solvation of the catalyst may work in opposition to the effect of basicity on the transition-state symmetry and therefore smooth out any variations in the isotope effect.” The manner in which steric interactions enhance k,/kD ratios has been discussed further by Lewis and Funderburk,18 in connection with additional measurements of proton abstraction from 2-nitropropane by pyridine bases. They argue that in addition to proton tunnelling (the isotope effect on Arrhenius A values evident from AdAD= 0.15) steric congestion of the transition state may also cause an abnormal loss of bending zero-point energy.A similar explanation could apply to the iodination of azulene. Less well authenticated claims have also been made that k,/k ratios effect the degree of proton transfer in the transition state (4)of base-catalysed Base .% H. L-c--$ / B a ’*x (4) p-elimination reactions.’ These appear to be substantiated by several recent findings. For instance there is nice agreement in the effect of substrate structure on the magnitudes of both the solvent isotope effect (ie. base = OH- and OD-in H,O and D,O respectively) and the primary isotope effect (i.e.k,,/kD for PhCH2CH2X us. PhCD2CH2X in solvent H,O) for E2 elimination from P-phenethyl derivatives consistent with the notion that both ratios depend on transition state symmetry. *’ More compelling evidence however is that primary k,/k ratios for OH-catalysed (3-elimination from PhCH,CH,SMei and PhCD,CH,SMel depend on the dimethyl sulph- oxide concentration in mixed-aqueous solvents passing through a maximum in about 50% dimethyl sulp%xi&.21 This is the first reported case of a maximum isotope effect for a single reaction. Related measurements of the leaving-group isotope effect (k32S/k34S)22 and other kinetic data” show the variation in k,/kn is consistent with the formation of a more reactant-like transition state (both C,-H and C,-S bonds only slightly stretched) in the dimethyl sulphoxide-rich solvents.Why the C,-H bond stretching should vary with solvent composition is less clear. Cockerill and Saunders” propose that addition of dimethyl sulphoxide desolvates and therefore raises the basicity of the OH- catalyst mainly on the grounds that a comparable solvent effect is not observed in either the Bu‘O-catalysed elimination from 2-aryl- ethyl bromide23 or the OH -catalysed elimination from fluorenyl nitrate.24 E. Grovenstein and F. C. Schmalsteig J. Amer. C~PIII. Soc. 1967.89. 5084. ** E. S. Lewis and L. H. Funderburk. J. Artier. Cheni. So(..,1967,89 2322. l9 J. F. Runnett. Angew. Chem. Inrernrit. Edri.. 1962. 1. 225. lo L. J. Steffa and E. R. Thornton J. Amer. Chem. SOC. 1967,89,6149.21 A. F. Cockerill J. Chem. SOC.(B),1967,964. 22 A. F. Cockerill and W. H. Saunders J. Amer. Chem. SOC. 1967,89,4985. 23 A. F. Cockerill S. Rottschaefer and W. H. Saunders J.Amer. Chem. SOC. 1967,89 901. 24 P. J. Smith and A. N. Bourns Canad. J. Chem. 1966,44,2553. Reaction Mechanisms I03 Also there is plenty of other evidence showing that dimethyl sulphoxide alters substrate basicities’’ and causes remarkable changes in the rates26 and isotope effects2’ of proton-transfer reactions. These observations therefore suggest that suitable studies in aqueous dimethyl sulphoxide solvents may be the easiest way of testing the current theories of primary-isotope effects. Solvent isotope efSects. The underlying theory to kinetic and equilibrium measurements in H,O-D,O mixtures has been substantially modified in recent years and the relevance of these changes is discussed by Albery28 in an authoritive review.However slight changes will be necessary in the theory and numerical calculations on account of experimental confirmation that the equilibrium constant for the fractionation of hydrogen isotopes in H20 and D,O [equation (l)] does not accord with the rule of the geometric mean (i.e. K = 4.0). H20 + D,O + 2HD0 The new experimental value (K = 3~75)~~ is in good agreement with that measured last year.30 The equilibrium constant (L)for equation (2) has been redetermined from electrochemical data and the new value of L = 9.0 & 0.3 also stands in excellent agreement with previous estimates.31 2D30+ + 3H20 + 2H30+ + 3D20 (2) It is generally recognised that measurements in H,O-D,O mixtures are not a reliable criterion of reaction mechanism but useful information as to the extent of proton transfer from the hydronium ion can be obtained for reactions in which this process is rate-controlling. [equation (Z)]. The degree of proton transfer (defined as aiand with values 0 < ai < 1) is obtained from the experimental measurements via equations which describe the resemblance between isotopic hydrogens (I.,) in the transition state with those in the solvent. Despite the complexity of these equations their applica- tion is straightforward as is shown in ref. 28. The magnitude of aishould by definition be similar to the Bronsted para- meter (a,) obtained from kinetic studies of general acid catalysis.Nevertheless their exact correspondence has been questioned because the energy differences upon which the two parameters depend are fundamentally different (a comes 2s (a) C. D. Ritchie and R. E. Uschold J. Amer. Chem. SOC. 1967 89 1721; (b) ibid. p. 2752; (c)E. C. Steiner and J. D. Starkey ibid. p. 2751. z6 C. D. Ritchie and R. E. Uschold J. Amer. Chem. SOC. 1967,89 1730. ’’ J. R. Jones Chem. Comm. 1967,710. 28 W. J. Albery Progr. Reaction Kinetics 1967,4 353. 29 J. W. Pyper R. S. Newbury and G. W. Barton J. Chem. Phys. 1967,46,2253. 30 L. Friedman and V. J. Shiner J. Chem. Phys. 1966,44,4639. 31 P. Salomaa and V. Aalto Acta Chem. Scand. 1966,20,2035. 104 B. C. Challis from differences of two potential energy surfaces whereas airefers to zero- point energy differences for a single potential energy surface).Recent ex-perimental studies however show substantial agreement between aiand aB for several reactions such as the hydrolysis of vinyl ethers32 including the related cyanoketen dimethylacetal [NC-CH=C(OMe)2],33 and the hydra- tion of a-methyl~tyrene.~~ Also aB for the acid-catalysed cleavage of allyl- mercuric iodide agrees with a obtained from earlier measurement^.^' Thus solvent isotope effects in H,O-D,O mixtures appear to be a useful alternative to the Bronsted technique of estimating transition state configurations. In connection with this conclusion claims have also been made that entropies of activation (AS#) also reflect the extent of proton transfer in the transition 36 It is suggested that ASfjdecreases with increasing proton transfer.The general utility of this criterion is doubtful as an extensive compilation of A-&2 reactions shows a rough correlation of AS# with sub- strate reactivity but in the opposite sense to that predicted above.37 Also polar substituents are known to interact with the solvent to cause drastic changes in AS#values.38 Solvent isotope effects in solvolysis reactions have been reviewed again this time by a proponent of the importance of initial-state s~lvation.~’ Studies of triphenylcarbinol ionization in H2S04 and D2S04show the HRfunction has the same numerical value in both solvents :40 this unexpected result is similar to that for the Ho function (amine equilibria) several years Secondary isotope effects.The origin of secondary isotope effects has been a controversial matter for some time. Generally speaking however they have been discussed in just two different ways either as non-bonded (steric) inter- actions (on the basis that C-D bonds are shorter than C-H bonds) or as electronic interactions of inductive or hyperconjugative types depending on the site of isotopic substitution. Key references for these two interpretations were given in last year’s report in which recent arguments in favour of the steric model were also summari~ed.~~ But the issue is far from settled parti- cularly in regard to P-deuteriation. Thus recent findings of ring deuteriation at any site increasing the stability of triphenylcarbonium ions,43 but decreasing the rate of proton-abstraction from toluene ~ide-chains,~~ both show that 32 (a)A.J. Kresge and Y. Chiang J. Chem. SOC.(B),1967,53,58;jb) P. Salomaa A. Kankaanpera and M. Lajunen Acta Chem. Scad. 1966,u) 1790. 33 V. Gold and D. C. A. Waterman Chem. Comm. 1967,40. 34 J-C. Simandoux B. Torck M. Hellin and F. Coussemant Tetrahedron Letters 1967 2971. 35 M. M. Kreevoy T. S. Straub W. V. Kayser and J. L. Melquist J. Amer. Chem. SOC. 1967,89 1201. 36 A. J. Kresge Y. Chiang and Y. Sato J. Amer. Chem. SOC.,1967,89,4418. 37 M. A. Matesich J. Org. Chem. 1967,32 1258. 38 A. C. Ling and I‘ H. Kendall J. Chem. SOC.(B),1967,440. 39 R. E. Robertson. Progr. Phys. Org. Chem. 1967,4213.40 E. DE Fabrizio Ricercu xi. 1966,36 1321. 41 E. Hogfeldt and J. Bigteison J. Amer. Chem. SOC. 1960,82 15. 42 Ref. 9 p. 280. 43 A. J. Kresge and R. J. Preto J. Amer. Chem. SOC.,1967,89,5510. 44 A. Streitwieser and J. S. Humphrey J. Amer. Chem. Soc. 1967,89 3767. Reaction Mechanisms I05 deuterium acts as an electron-donator (relative to hydrogen) with steric interactions playing only a minor part in these cases. A similar conclusion is drawn by Karabatsos and his colleagues45 for P-deuteriated systems such as SN1 solvolysis of (CD,),CCl and CD,COCl where hyperconjugative stabi- lisation should be important. Other studies of P-deuterium effects in t-butyl radical formation46 and nucleophilic substitution in allenyl halides4’ have also been interpreted in terms of hyperconjugative rather than steric differences between hydrogen isotopes.Therefore current results by and large serve to temper the recent views of H. C. Brown and his co-workers4’ on the overiding importance of steric effects. Another important development comes from hypotheses that charge de- localisation in the transition state reduces the usual magnitude of both a-and P-deuterium effects observed in limiting (SN1)solvolyses and that this re- duction might therefore be a useful probe for neighbouring-group participation. The case for P-deuterium is the better authenticated. Thus k,lkD ratios for the solvolysis of many 0-deuteriated cyclopropyl and cyclobutyl compounds such as (5) and (6) are much less than the usual value of k,/kD = 1.14 per P-deuterium atom observed for S,1 reactions.This reduction has been identified with substitution uin a common intermediate (7) in which charge ,-fD3 slow -products delocalisation lowers the usual demand for hyperconjugative stabilisation by the P-methyl groups.48 Arguments for a similar reduction of k,,/k ratios for a-deuteriation come from solvolysis studies of 2-arylethyl compounds known to react uia bridged phenonium ions (8). In this case the reduction in k,/kD is associated with the more ‘SN2-like’ transition state. which in turn should cHi-CD2-. -X-(8) 45 G. J. Karabatsos G. C. Sonnichsen C. G. Papaioannou S. E. Scheppele and R. L. Shone J. Amer. Chem. SOC.,1967,89,463. 46 T. Koenig and R.Wolf J. Amer.Chem. SOC.,1967,89 2948. 47 V. J. Shiner and J. S. Humphrey J. Amer. Chem. SOC.,1967,89,622. 48 M. NikoletiC S. BorEiE and D. E. Senko Tetrahedron 1967,23 649. 106 B. C. Challis reduce the usual a-deuterium effects ascribed to the relief of non-bonded interactions by the change from sp3 to sp2 hybridization in S,1 solvoly~is.~~ These suggestions have an important bearing on the much debated incidence of non-classical carbonium ions in the solvolysis of 2-norbornyl compounds. As is shown below for both a-and P-deuteriated species the exo-2-norbornyl brosylates (9) and (11) show significantly reduced k,/kD ratios whereas those for the corresponding endo-isomers (10) and (12) respectively are of the ex- pected magnitude for unassisted solvolysis.50~ 51 It is of importance too that 6-deuteriation of 2-norbornyl brosylates has a markedly different influence on the solvolysis rates of exo-isomers (13) and (14) compared to the endo- isomer (15).52None of these effects are inconsistent with the formation of D&OBs D &OBs D& OBs kJkD 1.14 1.10 1.oo (13)” (14)” (1 5)’’ bridged carbonium ions for the exo-brosylate isomers.Similarly reduced a-deuterium isotope ratios have also been reported for allylic rearrangements via cyclic transition states [equation (4)]. In this case the y-deuterium effect is inverse (kH/kD < 1). It is claimed that such effects may be a useful criterion for intramolecular allylic rearrangement^.^ 49 C. C. Lee and L. Noszk6 Canad. J. Chem. 1966,44,2491.C. C. Lee and E. W. C. Wong J. Amer. Chem. SOC.,1964,86,2752. 51 J. M. Jerkunica S. BorEiE and D. E. Sunko Chem. Comm. 1967 1302. ** B. L. Murr A. Nickon T. D. Schwartz and N. H. Werstiuk J. Amer. Chem. SOC.,1967,89,1731; J. M. Jerkunica S. BorEiE and D. E. Sunko ibid. p. 1732. 53 K. D. McMichael J. Amer. Chem. SOC.,1967,89 2943. Reaction Mechanisms 107 In an extensive compilation of recent data Seltzer and Zavitsas show that the magnitude of a-deterium secondary isotope effects for SN2 reactions are sensibly related to nucleophilic constants for both attacking and leaving groups.54 Acidity Functions and Molecular Basicity.-No major developments were reported in 1967 for either the theory of acidity functions or for their application to mechanistic problems in organic chemistry.For the records however new H values were determined for H2Se0,,55 HClO in mixed ~olvents,’~ and for EtOH-H2S0 mixtures using secondary amine indi~ators.’~ Other work has analysed activity coefficient behaviour of amide indicators (HAfunction) in H2S04,58 and this function also describes the protoQ.tion of heterocyclic N-oxides. Studies of diprotonation of phenylhydrazines aminopyridines and related compounds clearly show that as for motoprotonation of basic species molecular structure plays an important part in determining acidity function behaviour in acidic solvents.60 It is interesting to find that sulphon- amides are predominantly protonated on the nitrogen atom in contrast to 0-protonation for amides themselves indicating that considerable resonance occurs in the neutral species between sulphur &orbitals and the nitrogen lone pair electrons.61 The first direct measurement (using Raman spectro- photometry) of the basicity of methanol and propan-2-01 shows these com- pounds are 50% protonated in HCl at H values of -4.86 and -4.72 res-pectively.62 These figures should be used with discretion however in view of other equilibrium studies by Wells which suggest that both the above alcohols6 and other carbonyl compounds64 may exhibit considerably lower ‘pK’ values in very dilute acid.A substantial difference in the standard states for each set of measurements would account for the discrepancy. The first extensive measurement of the H-function in aqueous hydroxide solutions has been reported using substituted indole indicators ;65 these results lead to pK values for several biologically important pyrrole and indole derivatives.66 Other measurements of H-include those for aqueous dimethyl s~lphoxide~~ for methanol.68 Mechanistic implications of and 54 S.Seltzer and A. A. Zavitsas Canad. J. Chem. 1967,45,2023. ” S. Wasif J. Chem. SOC.(A),1967 142. 56 K. A. Boni and H. A. Strobel J. Phys. Chem. 1966,70,3771. ’’ D. Dolman and R. Stewart Canad. J. Chem. 1967,45,903. L. M. Sweeting and K. Yates Canad. J. Chem. 1966,44,2395. 59 C. D. Johnson A. R. Katritzky and N. Shakir J. Chem. SOC. (4,1967 1235. 6o P. J. Brignell C. D. Johnson A. R. Katritzky N. Shakir H. D. Turhan and G. Walker J.Chem. SOC. (4,1967 1233. 61 R. G. Laughlin J. Amer. Chem. SOC. 1967 SS 4268; F. W. Menger and L. Mandell ibid. p. 4424. 62 R. E. Weston S. Ehrenson and K. Heinzinger J. Amer. Chem. SOC. 1967,89,481. 63 C. F. Wells Trans. Faraday SOC. 1965,61,2194. 64 C. F. Wells Trans. Faraday SOC.,1967,63 147; cf. T. McTigue and J. M. Sime Austral. J. Chem. 1967 20 905. 65 G. Yagil J. Phys. Cheni. 1967,71 1034 1045. 66 G. Yagil Tetrahedron 1967,23 2855. 67 D. Dolman and R. Stewart Canad.J. Chem. 1967,45,911. 68 F. Millot F. Terrier and R.Schaal Compt. rend. 1966 263 C 1529. 108 B. C.Challis acidity function correlations for aromatic nucleophilic substitution have been discussed further and the results are analysed in terms of solvation-model explanations of the type developed earlier for acidic solutions.69 Also there seems to be considerable disagreement between measurements of hydrocarbon acidities in cyclohexylamine70 and dimethyl sulphoxide solvents.25a However relative acidities are similar in the two solvents and most of the discrepancies can be resolved by a suitable readjustment of the pK values for the reference corn pound^.^^^^^*^^ There is a rapidly growing interest in the basicity of molecules in electronic- ally excited states.Experimental studies of several aromatic hydrocarbons show both singlet and triplet states can be up to lo3’ times more basic than the ground in accord with theoretical calculations of lower n-electron localisation energies.73 In one instance the increase in basicity is reflected by a greatly enhanced rate of aromatic hydrogen exchange.74 For heteroaromatic species however the increases in basicity are much smaller7’ and this too accords with theoretical prediction^.^^" Substituent effects in the excited state have also been studied for both aromatic sulphur compounds76 and rn-nitro- aniline~.~’ The results are correlated by Hammett (PO)type equations and discussed in terms of enhanced electronic interactions. Substituent Effects.-Although the combination of resonance and polar (ix. non-resonance) interactions has offered a reasonably satisfactory ex-planation of substituent effects it has been evident for some time that this model requires revision in regard to the character and origin of the polar component.The nature of this revision has become apparent from recent work and is discussed below in connection with related interactions and the interpretation of substituent effects on n.m.r. data. Polar eflects. These have usually been described by the inductive model in which electronic interactions are propagated by successive polarisation of bonds linking the substituent to the reactive site. This polarisation may involve only the o-bond network (o-inductive effects) or in more refined treatments for unsaturated molecules the n-bond network as well (n-inductive effect^).^ * Various critics have assailed the inductive model mainly because of its inability to cope realistically with long range polar interactions i.e. those 69 F. Terrier and R.Schaal Compt. rend. 1967 264 C 465; C. H. Rochester J. Chem. Soc.(@ 1967,1076. 70 A. Streitwieser J. H. Hammons E. Ciuffarin and J. I. Brauman J. Amer. Chem. Soc. 1967 89 59; A. Streitwieser E. Ciuffarin and J. H. Hammons ibid..,p. 63. K. Bowden and A. F. Cockerill Chem. Comm. 1967,989. 72 M. G. Kuz’min B. M. Uzhinov and I. V. Berezin 2hur.jiz. Khim. 1967,41,446; R. L. Flurry and R. K. Wilson J. Phys. Chem. 1967,71 589. 73 R. L. Flurry J. Amer. Chem. Soc. 1966,88 5393. 74 M. G. Kuz’min B. M. Uzhinov G. Sentd’erdi and I. V. Berezin 2hur.jiz. Khim. 1967,41 769. 75 (a)N. Tyutyulkov F. Frater and D. Petkov Theor. Chim. Acta 1967 8 236; (b)R. Cetina D. V. S. Jain F. Peradejordi 0.Chalvet and R. Daudel Compt. rend. 1967 264 C 874. 76 E. L. Wehry J. Amer.Chem. Soc. 1967,89,41. 77 J. P. Idoux and C. K. Hancock J. Org. Chem. 1967,32 1935. ’* (a)M. J. S. Dewar and P. J. Grisdale J. Amer. Chem. Soc. 1962,84 3539 3548; (b)J. N. Murrell S. F. A. Kettle and J. M. Tedder ‘Valence Theory,’ J. Wiley London 1965 ch. 6. Reaction Mechanisms 109 at more than two C-C bond lengths. Instead it has been suggested that long range polar interactions at least are better represented by the field effect in which the electronic perturbation arises from direct electrostatic interaction across space between the substituent bond dipole and the reactive 79 Substantial evidence for the importance of field effects was summarised last year." Even more persuasive evidence comes from two recent investiga- tions by Stock and his co-workers'' on the acidity of several carboxylic acids [(16)+20)] for which the alternative models for polar interactions lead to entirely different predictions.The experimental data for one series of acids (16) are listed below where it can be seen that electron-withdrawing sub- stituents (-C1,-CO,CH etc.) decrease the acidity. The implicit destablisation &$$ \ \ pJyJ \ \ X (19) of the anion the reverse of the 'normal' substituent effect is consistent with the dipolar field but not the inductive model. The same conclusion may be Substituent (X) pK (stat. corrected) H 6-04 c1 6.25 COZCH 6.20 CO,H 5.97 c0,-6.89 drawn from the unusually small destablising influence of the CO -substituent pK(C0 -)/pK(H) = -0-85)."" Stock and his co-workers81b have also examined other acids [(17)+20)] in which the number of potential paths for o-inductive and n-inductive interactions is different.The effect of any sub- stituent is much the same in all these acids suggesting again that polar inter- 79 K. Bowden Canad. J. Chem. 1963,41,2781. Ref. 9 p. 283. *' (a)R. Golden and L. M. Stock J. Amer. Chem. SOC.,1966,88,5928;(b)F. W. Baker R. G. Parish and L. M. Stock ibid. 1967,89 5677. 110 B. C. Challis actions arise from a field effect rather than from any kind or combination of inductive effects. One other important point emerges from these" and related studies:82 the results can only be satisfactorily rationalised if the field asso- ciated with the polarised substituent depends on the direction of this bond which implies that the field is dipolar in character along the lines first suggested by Westheimer and Kirk~ood~~ rather than the point charge envisioned by Dewar and Grisdale more recently.78a This in turn accounts for the failure of the Dewar and Grisdale treatment with 8-substituted f3-naphthoic acids noted earlier by Wells and Adco~k.~~ The relative importance of n-inductive effects remains uncertain.These have been examined further by n.m.r. studies of 4-substituted 3,5-dimethyl- benzenes (21) in which polar effects should predominate because of steric hindrance to resonance. It is claimed the remaining interactions are best X CH3-C-CH, II MeoMe H F+ (3vF+ 3 explained by the dipolar field model with n-inductive effects contributing less than 2.5 %.85 However allowance for n-inductive effects in localised-orbital theory clearly permits a better account of substituent effects on both molecular properties and reactivity in benzene derivatives,86 and a similar conclusion is drawn from spectral studies of iodo- and iodoxy-benzenes.87 Several other experimental studies bear on the discussion above. One is concerned with electron-withdrawal by various cyano-carbon groups which is best acribed to a combination of dipolar field and resonance effects.88 Various suggestions have been advanced to account for the powerful deactiva- tion by the CF sub~tituent,~~ but recent arguments again favour a strong dipolar field effect.g0 These are considerably strengthened by the finding that fluorine hyperconjugation [an alternative explanation ;cf.equation (5)] is not important in carbanion formation a to the CF sub~tituent.~~ However the rapid attenuation of alkyl group polar effects with distance compared to other substituents has been associated with hyperconjugative delocalisation of W. Adcock and M. J. S. Dewar J. Amer. Chem. SOC.,1967,89,379. 83 J. G. Kirkwood and F. H. Westheimer J. Chem. Phys. 1938 6 506; F. H. Westheimer and J. G. Kirkwood. ihid p. 513. 84 P. R. Wells and W. Adcock Austral.. J. Chem. 1965 18 1365. 85 M. J. S. Dewar and Y. Takeuchi J. Amer. Chem. SOC. 1967,89,390. 86 M. Godfrey J Chem. SOC.(4,1967,799. 87 Z. Gakovic and K. J. Morgan J. Chem. SOC.(8, 1967,416. W. A.Sheppard and R. M. Henderson J. Amer. Chem. SOC. 1967,89,4446. 89 W. A. Sheppard J. Amer. Chem. SOC.,1965,87,2410. 'O M. J. S. Dewar and A. D. Marchand J. Amer. Chem. SOC.,1966,88,354. 91 A. Streitwieser A. D. Marchand and A. H. Pudjaatmaka J. Amer. Chem. SOC.,1967,89,694; A. Streitwieser and D. Holtz ibid. p. 693. Reaction Mechanisms (5) charge on the carbon chain rather than o-inductive or dipolar field ex- planations.92 p-n Interactions. Back donation of lone pair electrons or p-z interaction [equation (6)] has often been suggested to account for anomalously low electron withdrawal by polar first row substituents such as -F -OR and -NR2. This donation is usually associated with unsaturated residues and has been cited as such in recent investigations of carbanion stability,93 e.s.r.studies of o-trifluoromethylnitrobenzene radical^,'^ and also to explain the unexpected stability of fluorocarbonium ions [(22t(23)].95 However a recent theoretical reappraisal of polar effects (SCMO-CNDO method) leads to the unusual prediction that o-inductive effects of -F -OR and -NR2 sub-stituents result in charge alternation (24) rather than the usual steady decay (25) of charge along the carbon chain. The alternation is associated with back 6-6+ 66-66+ 6-6+ 66+ 666+ FtCtCtC FtCtCcC (24) (25) donation of lone-pair electrons which suggests this effect may be a feature of saturated as well as unsaturated systems. 96 N.m.r. measurements. The interpretation of n.m.r. chemical shift data has an important bearing on discussions of polar interactions and Dewar has continued his detailed analysis of the problem with studies of substituted 1-and 2-fl~oronaphthalenes.~~ The 19F chemical shifts for these compounds can only be rationalised satisfactorily in terms of resonance and dipolar field interactions if the major contribution to the latter results from lengthwise polarisation of the C-F bond.This would explain why substituent effects of I9F chemical shifts are qualitatively different from those on physical or 92 P. E. Petersen R.J. Bopp. D. H. Chevli E. L. Curran. D. E. Dillard and R.J. Kamat. J. Arwr.. Charti. So<,..1067.89. 5902. 93 J. Hine L. G. Mahone and C. L. Liotta J. Amer. Chem. SOC. 1967,89 5911. 94 L. G. Janzen and J. L. Gerlock J.Amer. Chem. SOC.,1967,89,4902. Chem G. A. Olah R. D. Chambers and M. B. Comisarow,J. Amer. Chem. Soc. 1967,89,1268. 96 3. A. Pople and M. Gordon J. Amer. Chem. SOC.,1967,89,4253. 112 B C. Challis chemical properties of other side chains. Thus Dewar and AdcockS2 conclude that both sets of phenomena cannot be treated by a common scheme involving o-inductive and resonance effects as suggested eaiiier by Taft97 for substituted fluorobenzenes. Two recent discussions of solvent effects in "F n.m.r. cor- relations also bear on this problem.98 Nevertheless there is further evidence of reasonable correlations between 19Fchemical shift data and Hammett oPparameters from studies of carbonyl group electron densities" and heats of formation for Lewis acid adducts'" of benzophenones and also for hydrogen bonding between p-fluorophenols and various acceptors;"' in two cases the results are corroborated by data from other independent measurements.'00.'02 To summarise the situation it seems unlikely that the exact nature of component electronic interactions influencing chemical reactivity will be discernable from 9F n.m.r. measure- ments. This data may however provide reliable estimates of Hammett a,-parameters for benzene derivatives. It is also evident that similar comment applies to 1H85,103 and 13C104 chemical shift data. Here again reasonable correspondence between para-H chemical shifts and 0,-parameters can be obtained,'05 but the correlations break down for substituents at other sites.Dewar and Take~chi~~ conclude that because 'H chemical shifts are more sensitive to long-range magnetic interactions the general treatment of this data in terms of substituent inter- actions may be even less successful than for "F chemical shifts. This does not mean that empirical correlations will have no value as is evident from? statistical treatment of orientation in substituted pheno1s.'O6 Also attempts to account for some of these perturbations have been made for heteroaromatic systems and 'H chemical shifts then c rrelate reasonably well with calculated electron densities.lo7 It is of interest to note too that chemical shifts of side- chain protons may also prove a morg usefuk method of estimating chemical reactivity ; several satisfactory correlations have been noted for phenols,"' 97 R.W. Taft J. Phys. Chem. 1960,64 1805. 98 J. W. Emsley and L. Phillips Mol. Phys. 1966 11 437; H. M. Hutton B. Richardson and T. Schaeffer Canad. J. Chem. 1967,45 1795. 99 R. G. Pewes Y. Tsuno and R. W. Taft J. Amer. Chem. SOC. 1967,89,2391. loo G. S. Giam and R. W. Taft J. Amer. Chem. SOC.,1967,89 2397. lo' D. Gurka R. W. Taft L. Joris and P. von R. Schleyer J. Amer. Chem. SOC.,1967,89 5947. lo* Cf. E. M. Arnett T. S. S. R. Murty P. von R. Schleyer and L. Joris J. Amer. Chem. SOC.,1967 89 5955. lo3 J. C. Schug J. Chem. Phys. 1967 46 2447; J. M. Read and J. H. Goldstein J. Mol. Spectro-scopy 1967,23 179. K. S. Dhami and J. B. Stothers Canad. J. Chem. 1966,4,2855; T. D. Alger P. M. Grant and E. G. Paul J.Amer. Chem. SOC.,1967,89 5397. lo' H. P. Figeys and R. Flammang Mol. Phys. 1967 12 581; D. T. Clark and J. W. Emsley ibid. p. 365. lo6 J. A. Ballantine and C. T. Pillinger Tetrahedron 1967,23 1691. lo' P. J. Black R. D. Brown and M. L. Heffernan Austral. J. Chem. 1967 20 1305 1325; R. J. Chuck and E. W. Randall J. Chem. SOC. (B) 1967 262; E. J. Vincent R. Phan-Tan-Luu and J. Metzger Bull. SOC. chim. France 1966 3537; W. Adam and A. Grimison Theor. Chim. Acta 1967 7 342. lo* J. G. Traynham and G. A. Knesel J. Org. Chem. 1966,31,3350. Reaction Mechanisms carbinols,'Og benzoic acids,'" and styrenes.' ' In these cases either magnetic and electric field effects cancel or they are rapidly attenuated with distance from the nucleus. Linear Free Energy Relationships.-The utility of various substituent-dependent energy parameters to explore the mechanism of organic reactions continues to attract considerable attention.Much of this is concerned with the development of the Hammett and Ingold-Taft relationships but new approaches have been reported. One of the most interesting suggestions comes from Thornton,"' who has outlined a simple theory for predicting substituent effects on transition-state geometry by considering these as linear perturbations of the vibrational potentials for normal co-ordinate motion both parallel with and perpendicular to the motion along the reaction co-ordinate. The one difficulty of course is deciding which mode is the reaction co-ordinate. Nevertheless simple rules for estimating both effects are given and the treatment is discussed in relation to substitution (S,j and elimination (E2j reactions.The influence of solvents on substituent effects has been considered in detail by Tommila''3 using an electrostatic model and the results lead to the con- clusion that electronic interactions are at least partly transmitted through the solvent. A more serious but not unexpected discrepancy is noted by Ceska and Grunwald,' l4 who find appreciable qualitative differences between substituent parameters determined from amine equilibria in water and organic solvents (such as alcohols and acetic acid). This leads to the suggestion that linear free- energy correlations of reactivity for non aqueous solvents should be based on parameters derived from ion-pair formation in acetic acid rather than from ionisation equilibria in water.Other studies also comment on solvent dependent Hammett o-parameters which can be attributed generally to solvation effects on the ionisation equilibria.' ' In view of these findings it is interesting to note that relative reactivities of solid benzoic acids are roughly proportional to their acidities.'I6 Also several further correlations of mass-spectral ion-intensities with Hammett o-para- meters have been reported and it looks as if this technique will be valuable for mechanistic studies of some ion-decompositions in the gas phase. The method first outlined last year,'" is based on the assumption that mass-spectral pro- log R. J. Ouellette D.L. Marks and D. Miller J. Amer. Chem. SOC.,1967,89,913. Y. Kondo K. Kondo T. Takemoto and T. Ikenoue Chem. and Pharm. Bull. (Japan) 1966 14 1332. T. A. Wittstruck and E. N. Trachtenberg J. Amer. Chem. Soc. 1967 89 3803; R. Gurudata J. B. Stothess and J. D. Talman Canad. J. Chem. 1967,45,731. E. R. Thornton J. Amer. Chem. Soc. 1967,89,2915. E. Tommila Ann. Acad. Sci. Fennicae 1967 A No. 139 1. 'I4 G. W. Ceska and E. Grunwald J. Amer. Chem. Soc. 1967,89,1377. C. L. de Ligny Rec. Trau. chim. 1966 85 1114; P. D. Bolton F. M. Hall and I. H. Reece Spectrochim. Acta 1966 22 1825; C. H. Rochester and B. Rossall J. Chem. Soc. (B) 1967 743; A. Fischer G. J. Leary R. D. Topsom and J. Vaughan ihid. p. 686; p. 846. E. A. Myers E. J. Warwas and C. K. Hancock J.Amer. Chem. Soc. 1967,89 3565. 'I7 M. M. Bursey and F. W. McLafferty J. Amer. Chem. Soc. 1966,88,529,4484. 114 B. C.Challis cesses can be regarded as a set of competing consecutive unimolecular decompositions. Thus for the decomposition of a molecular ion M yielding a product ion A the effect of a substituent on the relative abundance ratio 2 (= [A]/[M])is given by equation (7) where X and H refer to substituted and parent compound respectively. Because of the absence of external solvation log ZJZ = po (7) both charge development in the transition state and therefore p values will be generally lower than for equivalent solution processes. Following up on last year's reports,' l7 full details have been published for the decomposition of benzoyl compounds."' It is evident that equation (7) is applicable to the elucidation of reactions leading to the product ion (A)through either a single reaction consecutive reactions or competing reactions when the product ion does not contain the substituent.If the product ion does contain the sub- stituent sensible prr correlations are only possible under low-energy conditions when further decomposition (also substituent dependent) is inappreciable. '' The technique has been used to investigate the mechanisms of the McLafferty rearrangement' in which the nature of the hydrogen migration is speculative. Studies of substituent effects in butyrophenones [equation (S)] show clearly that both electron-withdrawal (p = 2.0) and resonance stabilisation of charge by para-substituents increase the rate suggesting the incursion of two inter- mediates [(26)and (27)] in both of which development of the radical site is the / \ 'X f"0 / I 'I8 M.M. Bursey md F. W. McLafferty J. Amer. Chem. SOC.,1967 89 1; cf. F. W. McLafferty and M. M. Bursey Chem. Comm. 1967,533. (a) F. W. McLafferty and T. Wachs J. Amer. Chem. SOC. 1967,89 5043; (b)ibid. p. 5044. Reaction M echanisrns driving force for rearrangement.' This is partially consistent at least with other findings that the usual rearrangement process is completely inhibited by substituents (such as p-H,NC,H,[CH,],-) on which the positive charge and therefore the unpaired electron may localise. Linear correlations with equation (7) have also been reported for the mass-spectral decomposition of azobenzenes for which C-N bond cleavage is facilitated by electron withdrawal (p = 1-05),'20and for the decarboxylation of arylmethyl carbon- ates.' 21 Despite these results the general applicability of ground state sub- stituent parameters to excited state reactions is questionable particularly in view of Wehry's7 recent investigation which clearly shows that enhanced electronic interactions may feature in the excited state.Other recent work has concerned further extension of the Hammett equation via linear combinations of substituent parameters (on the lines of the Yukawa- Tsuno'22 treatment) to electophilic substitution and rearrangement^,'^^ base-catalysed hydrolysis,' 24 and free-radical reactions.' 25 The latter are shown to correlate well with equation (9) where the second term accounts for resonance interactions; E values are obtained directly from substituent effects on hydrogen abstraction from cumenes.Kinetic studies show the reactivity of various carbonyl compounds towards the hydrated electron correlates with Taft G* parameters and for aldehydes ketones and carboxylic acids p = -0-74. Amides and esters however deviate from this plot on account of resonance delocalisation of the electrophilic centre to either the nitrogen atom or the alkoxy oxygen atom. It is therefore suggested that electrophilic reactivity toward the hydrated electron may be a useful probe for exploring the electronic configuration of molecules.'26 Electrophilic Aromatic Substitution.-Of the many recent developments in these reactions only three topics have been selected for detailed discussion.These are certain aspects of the mechanism reflecting on the structure of possible intermediates substitution of positively charged substrates and re- arrangement reactions in electrophilic hydroxylation. Other significant findings are mentioned briefly below. As predicted in a recent review of reactions in molten salts,'27 the addition of pyrosulphate ions (S2072-) to alkali-metal nitrates increases the con-centration of NOz to synthetically significant concentrations [equation (lo)], + NO3-+ S2OT2-+2 SO,2-+ NOz+ (10) J. H. Bowie G. E. Lewis and R. G. Cooks J. Chem. SOC.(B),1967,621. P. Brown and C. Djerassi,J.Amer. Chem. Soc. 1967,89 2711. "' Y. Yukawa and Y. Tsuno Bull. Chem. SOC.Japan 1959,32,971. lZ3 Y. Yukawa Y. Tsuno and M.Sawada Bull. Chem. SOC.,Japan 1966,39 2274. A. A. Humffray and J. J. Ryan J. Chem. SOC.(B) 1967,468. T. Yamamoto and T. Otsu Chem. and Id. 1967,787. lZ6 E. J. Hart E. M. Fieiden and M. Anbar J. Phys. Chem. 1967,71,3993. ''' W.Sundermeyer Angew. Chem. Internat. Edn. 1965.4222. 116 B. C. Challis and smooth nitration occurs with many aromatic compounds including nitrobenzene. The aromatic substrates were passed into a mixture of doped nitrate salts at 300" via a stream of nitrogen gas.128 This process bears some resemblance to the reaction of arylchloroformates with silver nitrate which produces high yields of o-nitrophenols via rearrangement of the nitrato- carbamate formed initially [equation (1l)] ; with 2,6-disubstituted chloro-formates 4-nitro-products are obtained suggesting an intermolecular mech- anism.' 29 Unexpectedly large amounts of ortho-substitution are reported for the mixed-acid nitration of both neopentylbenzene (45 % o-i~omer)'~' and 0 0 I1 I1 R R R R 2,7-di-t-butylnaphthalene (56% l-isomer).'31 Since earlier studies132 have shown that bulky alkyl substituents usually inhibit o-nitration some special interaction between the reagent and side-chain is clearly indicated. Another recent paper records the first straightforward nitration of pentafluorobenzene by employing an HN03-BF3 mixture in tetramethylene sulphone ; previous attempts to nitrate highly fluorinated aromatic compounds have usually produced oxidation products such as quinones.' 33 Although many chlorination reactions of sulphuryl chloride are catalysed by free-radical initiators 134 there is now definitive evidence that this reagent reacts with reactive aromatic substrates (e.g.anisole and naphthalene) via a heterolytic path with electrophilic attack by molecular SO,CI,. 35 Also kinetic studies show the reaction of cresol with chloramine-T involves a dichloramine-T reagent rather than HOCI as has been presumed for many years; the reaction rate is independent of the cresol concentration because formation of the dimeric reagent is the slow step.'36 Other investigations have concerned hydrogen exchange in methoxy-benzenes12*36 and substituted NN-dimethylanilines.14 38 The isotope effects associated with these reactions are discussed in detail on p. 101. Further lZ8 R. B. Temple C. Fay and J. Williamson Chem. Comm. 1967,966. lz9 M. J Zubik and R. D. Schultz J. Org. Chem. 1967,32 300. D. F. Gurka and W. M. Schubert J. Org. Chem. 1966,31,3416. L. Erichomovitch M. MCnard F. L. Chubb Y. PCpin. and J-C. Richer Canad. J. Chem. 1966,442305. H. C. Brown and W. H. Bonner J. Amer. Chem. Soc.. 1954 76,605. P. L. Coe A. E. Jukes and J. C. Tatlow J. Chem. SOC., (C),1966,2323. 134 Cf. R. Stroh in Houben Weyl's 'Methoden der Organische Chemie' vol. V/3 p. 873. R. Boulton and P. B. D. de la Mare J. Chem. SOC. (B) 1967 1044; P. B. D. de la Mare and H. Suzuki J. Chem. SOC.(C) 1967,1586. 136 T.Higuchi and A. Hussain J. Chem. SOC.(B) 1967 549. Reaction Mechanisms studies of heterogeneous Group VIII metal-catalysed hydrogen exchange 13' including those for heterocyclic substrates,'37b are consistent with the x-dissociative mechanism discussed in last year's report. 38 An interesting development of this process is that similar hydrogen exchange also proceeds under homogeneous conditions with soluble Pt" and Pd" salts.'39 This is of particular value for substituted compounds (e.g. nitrobenzene) that usually 'poison' the conventional heterogeneous metal catalysts. Electrophilic substitution reactions in polyalkylbenzenes are discussed in an excellent review,14' from which it is evident that side-chain substitution in these compounds often results from a rate-determining substitution in the aromatic nucleus followed by rearrangement.It is noteworthy that several further examples of this kind of rearrangement have been recognised both for halogenation of l-methylnaphthalene'41 and p~lymethylbenzenes~~~ and for isotopic hydrogen exchange in anilinium ions. 143 Mechanism. Although there is little doubt that the majority of electrophilic aromatic-substitution reactions involve a two-step process [equation (12)] for which the o-bonded intermediate is stable relative to the transition-state various aspects of this mechanism provoke further inquiry. In only a few cases are the intermediates sufficiently stable to be isolated as with hindered phenols where dienone structures (28) are formed.144 The substituent effects on dienone formation have now been examined and they are remarkably similar to those for electrophilic substitution in phenol.This is good evidence that both reactions have similar o-bonded transition RH OR 137 (a) A. W. Weitkamp J. Catalysis 1966 6 431 ; B. D. Fisher and J. L. Garnett Austral. J. Chem. 1966 19 2299; C. G. McDonald and J. S. Shannon ibid.. 1967 20 297; (b) G. E. Calf and J. L. Garnett Chem. Comm. 1967,306. ''* Cf. Ref. 9 p. 291. 139 (a) J. L. Garnett and R. J. Hodges J. Amer. Chem. SOC. 1967 89 4546; J. L. Garnett and R. J. Hodges Chem. Comm. 1967 1220; (b) ibid. p. 1001. 140 E. Baciocchi and G. Illuminati Progr. Phys. Org. Chem. 1967,5 1. 14' G. Gum P. B. D. de la Mare and M. D. Johnson J.Chem. SOC.(C),1967,1590. 142 V. G. Shubin V. P. Chzhu A. I. Rezvukhin and V. A. Koptyug Izvest. Akad. Nauk S.S.S.R. Ser. khim. 1966 2056. 143 J. R. Blackborrow and J. H. Ridd Chem. Comm. 1967 132. 144 Cf. B. C. Challis Ann. Reports 1965,62,258. 118 B. C.Challis states.14' The intermediate (29) in the reaction of NN-dimethylaniline with tetracyanoethylene is stable enough for n.m.r. and spectral confirmation of its o-bonded str~cture.'~~ Further viability for the concept of o-bonded intermediates comes from several recent reports of phenonium ion formation in solvolysis rea~ti0ns.l~~ Of the many factors that may determine whether k or k is rate-controlling steric compression in the transition state appears to be of prime importance.Thus further evidence of substantial primary isotope effects for the bromination of polyalkylbenzenes is not surprising. 14* Decomposition of the o-bonded intermediate (k2)appears to be slow for the NOz+BF4- nitration of 9-r2H2]-anthracene (kH/kD = 2.6) and it is claimed that spectral measurements show formation of the o-complex is instantaneo~s.'~~ It has also been suggested from studies of acid-catalysed aromatic mercuration that the selectivity rule may not apply to reactions where k2 is the slow step.'" The question of rate-determining n-complex formation in some of these reactions (as a precursor to the o-bonded intermediate) continues to be debated. Much of the controversy centres on the unusually low substrate selectivities obtained from competitive experiments by Olah and his colleagues for aromatic nitration by nitronium salts.' '' Several subsequent experiments have indicated that these low values may arise from partial diffusion control of the reaction rates rather than slow .n-complex formation.' 52 Further kinetic studies of nitration in sulphuric acid support these indications by showing that compounds more reactive than benzene combine with NO2+ on en- counter.lS3 This finding may also explain the apparent breakdown of the additivity principle for the nitration of alkylbenzenes in acetic acid.154 The validity of other results obtained by competitive experiments is also under suspicion.Thus large discrepancies have been reported between the relative reactivities of benzene and toluene for Friedel-Crafts halogenation obtained by competition k(phCH3)/k(phH) 'V 3~6)'~~ and by independent kinetic measure- ments [k(ph,,,)/k(phH) = 381 ' under otherwise similar experimental con-ditions.Although n-complexes are formed between aromatic substrates and suitable electrophilic reagents as is evident from. for example other studies 14' E. Baciocchi and G. I!luminati J. Amer. Chem. SOC. 1967,89. 4017. 146 P. G. Farrell. J. Newton and R. F. M. White J. Chem. SOC.(B),1967,637. 14' G. A. Olah M. B. Comisarow E. Namanworth and B. Ramsay J. Amer. Chem. SOC. 1967 89,711,5259. 14' E. Baciocchi G. Illuminati G. Sleiter and F. Stegel J. Amer. Chem. SOC.,1967 89 125; A. Nilsson Acta Chem. Scand. 1967,21,2423. 149 H. Cerfontain and A. Telder Rec.Trav. chim. 1967,86,371. A. J. Kresge and H. C. Brown J. Org. Chem. 1967,32 745. G. A. Olah S. J. Kuhn and S. H. Flood J. Amer. Chem. SOC.,1961,83,4571; G. A. Olah S. J. Kuhn and S. H. Flood ibid. 1962,84 3687. B. C. Challis Ann. Reports 1966,63 296; ibid. 1965,62 257. R. G. Coombes R. B. Moodie and K. Schofield Chem. Comm. 1967,352. 154 A. Fischer J. Vaughan and G. J. Wright J. Chem. SOC.(B) 1967,368. G. A. Olah S. J. Kuhn S. H. Flood and B. A. Hardie J. Amer. Chem. SOC.,1964 86 1036; G. A. Olah S. J. Kuhn and B. A. Hardie ibid. p. 1055. 156 S. Y. Caille and R. J. P. Corriy Chem. Comm. 1967 1251. Reaction Mechanisms 119 of nitrosation,' 57 the case for their rate-controlling formation in nitration and Fnedel-Crafts halogenation is seriously weakened by the above results.On the theoretical side it has been shown that bromination rates for sub- stituted benzenes' 58 and polynuclear hydrocarbon^'^' correlate with various theoretical estimates of reactivity (e.g.localisation energies) and these results complete the correlations for the commoner electrophilic substitution re- actions. Their significance is of course the implication that o-complex formation is rate-controlling. Also it has been suggested that hyperfine coupling cpnstants (from e.s.r. studies) may prove an accessible measure of chemical reactivity and data for polynuclear hydrocarbons bears out the claim.'6o Positively charged substrates. The incidence of electrophilic substitution in the conjugate acids of aromatic amines was first recognised unambiguously about five years ago for the nitration of anilinium salts.'61 Subsequent evidence has shown this unexpected reaction to be fairly common for aromatic species in concentrated acids and for basic hetero-aromatic compounds under less stringent conditions.Details of the nitration of sulphonium and selenium have now been pub- lished,'62 and the product orientations are listed in Table 3 together with earlier results for the mononitration of other 'onium salts. The implications of TABLE 3 Nitration of 'oniumsalts Product Orientation ( %) Ref ortho meta para ArNMe,' 163 -89 11 ArPMe,' 163 -97 3 ArAsMe,' 163 -96 -4 ArOAr ' 164 -100 ArSMe,' 162 3.6 90.4 6.0 ArSeMe,' 162 2.6 91.3 6.1 these data in terms of substituent interactions are incompletely understood.Arguments have been advanced that electrostatic factors are of overiding importance for the anilinium salts,165 and this conclusion is supported by further theoretical calculations.'66 Presumably the same will be true for other groups but the situation must be modified by the possibility of p-and d-lS7 Z.J. Allan J. Podstata D. Snobl and J. Jarkovsky Coll. Czech. Chem. Comm. 1967,32 1449. lS8 J-E. Dubois and J-P.Doucet Tetrahedron Letters 1967,3413. 159 L. Attschuler and E. Berliner J. Amer. Chem. Soc.. 1967.89.5837. 160 C. P. Poole and 0.F. Griflith J. Phys. Chem. 1967,71 3672. 16' M. Brickman S. Johnson and J. H. Ridd Proc. Chem. SOC.,1962,228. 162 H. M. Gilow and G. L. Walker J. Org. Chem. 1967,32,2580 163 J.H. Ridd and J. H. P. Utley J. Chem. SOC.,1964,24 164 N. N.Nesmayanov T. P.Tolstaya L.S.Isaeva and A. V. Grid Doklady Akad. Nauk S.S.S.R. 1960,133,602. 165 J. H. Ridd Chem. SOC.Spec. Publ. No. 21 1967 p. 149. 166 R. Reynaud Compt. rend. 1967,264 C 1723; D. R. Williams Mol. Phys. 1967,12 33,41. 120 B. C.Challis orbital interactions. For instance electron-withdrawal via d,-p interaction (-M) should lead to enhanced rneta-substitution for all groups other than NMe,' whereas pn-p electron donation (+M) only possible for OMe,+ SMe,' and SeMe2+ would explain the increased tendency for ortho-and para-su bs t it ution. Further evidence of electrophilic substitution in anilinium ions come from isotopic hydrogen exchange in 95% D,S04.In the presence of strongly activating groups (e.g. -0Me) the positive pole appears to have no marked directing effect and exchange rates are remarkably similar for ortho- rneta and para-positions.143 Related experiments show that N-proton exchange with the solvent is much slower than nuclear nitration at the same acidity. This removes any remaining doubt that the nitration may proceed through the microscopic amounts of unprotonated amine at these high a~idities.'~~ Several recent papers have reported on electrophilic substitution in hetero- aromatic cations and salts. These results help to explain unusual products from several reactions arising either from perturbation of the electron distribution or from the blocking of reactive sites in the free organic base.For instance substi- tution of the indole nucleus in concentrated acids occurs predominantly on the aromatic ring rather than the 3-position which is extensively protonated under these conditions.'68 Two recent reviews deal with substitution in six- membered hetero-aromatic cations from the synthetic' 69a and mechanistic standpoint^,'^^' but these are already outdated by further developments. There is clear-cut kinetic evidence that activated pyridinium cations undergo both nitration and hydrogen exchange in concentrated acids. Thus 2,4,6-trimethyl- 2,4-dimethyl- 2,6-dimethyl- and 3,5-dimethoxypyridines all mononitrate as their respective cations. '70 Deactivated isomers however such as nitro- and 2,6-dichloro-pyridine react only as their free bases.70 Also nuclear hydrogen exchange in amino-pyridines occurs via the pyridinium cation,17' and this is consistent with conclusions drawn from the N-nitro-sation of amino-pyridines in concentrated perchloric acid.' 72 These results lead Katritzky and his colleagues170b to predict that basic pyridines (pK > 1)will generally react as cations whereas feebly basic pyridines (PK,< -2.5)will only undergoe substitution as a free base; in both instances the orientation will be to the a-or p-sites depending on other substituents. It is of interest to note however that an alternative mechanism [equation (13)] involving an ylid intermediate (30) has been sugested to account for the smooth exchange at the 2-and 6- positions of pyridine in dilute DCl.17 The reactivity of the S.R. Hartshorn and J. H. Ridd Chem. Comm. 1967 133. W. E. Noland K. R. Rush and L. R. Smith J. Org. Chem. 1966,31,65; B. Bak C. Dambmann and F. Nicolaisen Acta Chem. Scand. 1967 21 1674. 16' (a)R. A. Abramovitch and J. G. Saha Adu. HeterocycZic Chem. 1966,5,229;(b)A. R. Katritzky and C. D. Johnson Angew. Chem. Internat. Edn. 1967,6,608. 170 (a) C. D. Johnson A. R. Katritzky and M. Viney J. Chern. SOC. (B) 1967 1211; (6) C. D. Johnson A. R. Katritzky B. J. Ridgewell and M. Viney ibid. p. 1204. 17' G. P. Bean C. D. Johnson A. R. Katritzky B. J. Ridgewell and A. M. White J. Chem. SOC.(B) 1967,1219. 17* E. Kalatzis J. Chem. SOC.(B) 1967 273 277. J. A. Zoltewicze and C. L. Smith J. Amer. Chem. SOC. 1967,89 3358. Reaction Mechanisms D D (30) pyridine nucleus towards nitration has also been discussed and roughly speaking for several substituted derivatives the base and cation are less reactive than the corresponding derivatives of benzene by factors of lo2 lo3 and lo7,re~pectively.'~' Related investigations of nitration 174 and hydrogen exchange'75 on pyridine-N-oxides show that substitution occurs in the 4-position with the neutral molecule and in the 3-position of the conjugate acid.However an important anomaly remains-under similar experimental conditions nitration preferentially proceeds through the free base whereas the usually more selective hydrogen exchange attacks the more abundant but less reactive con- jugate acid at the 3-position. Qualitative studies reveal a similar anomaly for nitration and hydrogen-exchange of quinoline-N-oxide.' 76 No satisfactory explanation of this phenomenon has been given but Katritzky and J~hnson'~' note that any further destabilisation of the double-charged Wheland inter- mediate (31) for 3-substitution (such as electron-withdrawal by the nitro- group) would make this pathway much less favourable than that for 4-substitution (32).+ (yo2 pj2 I II OH 0 (31) (12) Other pertinent investigations have examined acid-catalysed nitration and hydrogen exchange in . pyridones,' 779 '78 quin~lines,'~~ and pyr~nes'~~ thiapyrones. '78 Collectively these results show that electrophilic substitution occurs in both the free base and the conjugate acids of the N-heterocyclics (depending on the experimental conditions) but only in the free base of the S-and 0-heterocyclic analogues.Thus the relative effects of NH' 0' and S+ in these six-membered rings show an interesting parallelism with those of NH 0 and S in five-membered heteroaromatic cornpo~nds.'~~ Also some unexpected results for hydrogen exchange in 4-pyrimidone~'~' and nitration 17* C. D. Johnson A. R. Katritzky N. Shakir and M. Viney J. Chem. SOC.(B) 1967 1213. 17' G. P. Bean P. J. Brignell C. D. Johnson A. R. Katritzky B. J. Ridgewell H. 0.Tarham and A. M. White J. Chem. SOC.(B),1967,1222. 17' Y. Kawazoe and M. Ohnishi Chem. and Pharm. Bull (Japan),1967,15,826. 177 P. Bellingham C. D. Johnson and A. R. Katritzky J. Chem. SOC.(B),1967 1226. P.Bellingham C. D. Johnson and A. R. Katritzky Chem. Comm. 1967 1042. 179 G. E. Wright L. Bauer and C. L. Bell J. Heterocyclic Chem. 1966,3,440. 122 B. C. Challis of 4-phenylpyrimidine180 may reflect the importance of substitution via their conjugate acids. Electrophilic hydroxylation. An unexpected intramolecular rearrangement of deuterium appears to accompany the peracid hydroxylation of [4-2H]-acetanilide [equation (14)l. NHAc NHAc (7.5%) (14) H D (33) (34) Similar deuterium migration is not observed in other electrophilic substitu- tions (e.g. nitration and bromination) of the anilide thus the key step appears to be smooth formation of the dienone (34) from the cr-bonded intermediate (33).181 This rearrangement has an analogy in the formation of dienones via methyl migration in the related hydroxylation of alkylbenzenes.Although it is just conceivable that the deuteriated product could arise by an inter- molecular process other evidence suggests this is unlikely and also indicates that hydrogen migration may be a common feature of reactions involving phenolic cations such as (33). Thus the acid-catalysed dehydration of 3-chloro-6-deuterio-5,6-dihydroxy-i,3-cyclohexadiene gives 4-chlorophenol containing about 20'4 deuterium in the 3-position [equation (1 5)].183 Also rapid 4-deuteri- ation is reported for 5-hydroxyindole and several of its derivatives in D,O. Other hydroxyindoles however undergo substitution in the aromatic ring at a much slower rate.184 Although it is well established that both pr~tonation'~~ and hydrogen exchange186 occur at the 3-position of the indole nucleus the next most reactive site towards electrophiles is the 5-position.Presumably sufficient protonation occurs here with 5-hydroxyindole for deuterium B. M. Lynch and L. Poon Canad. J. Chem. 1967,45 1431. D. M. Jerina J. W. Daly W. Landis B. Witkop and S. Udenfriend J. Amer. Chem. SOC. 1967,89,3347. lE2 H. Hart P. M. Collins and A. J. Waring J. Amer. Chem. SOC.,1966,88,1005; H. Hart and R. M. Lange J. Org. Chem. 1966,31 3776. lS3 D. M. Jerina J. W. Daly and B. Witkop J. Amer. Chem. SOC.,1967,8!2,5488. J. W. Daly and B. Witkop J. Amer. Chem. SOC.,1967,89 1032. "5 R. L. Hinman and E. B. Whipple J. Amer. Chem. SOC.,1962,84 2534. lS6 B.C. Challis and F. A. Long J. Amer. Chern. SOC. 1963,85,2524. Reaction M echanisms c1 c1 migration to proceed. The significance of this finding in relation to enzymatic hydroxylation which may also involve dienone formation from a cationic intermediate has also been discussed.’*’ ‘13’ S. Udenfriend P. Zaltman-Nirenberg J. W. Daly G. Guroff C. Chidsey and B. Witkop Arch. Biochem. Biophys. 1967,120,413. E