4 Reaction Mechanisms Part (ii) Polar Reactions By D. G. MORRIS Department of Chemistry The University Glasgow G12 8QQ 1 Introduction The present Report covers nucleophilic substitution carbo-cations carbanions nucleophilic addition to carbonyl compounds and to olefins reactivity of esters and of carbodi-imides and elimination reactions. Two significant reviews one on intramolecular catalysis’ and one entitled ‘When is an intermediate not an intermediate’,2 have appeared. A very readable review of methods of esterification and carbonyl protection has been given.3 Other reviews of note concern the use of reactive and selective leaving groups (e.g. PhCOOS02CF3) which obviate the necessity for Friedel-Crafts catalysis displacement reactions of allylic corn pound^,^ and a -acyl carbo-cations.6 2 Nucleophilic Substitution A perturbational study using Salem’s frontier-orbital method of bimolecular nucleophilic substitution at saturated carbon has been carried out to determine conditions under which the reaction can proceed with retention of configuration.’ Such a stereochemical outcome though of course never observed at saturated carbon is favoured by low electronegativity at the reaction centre a hard nucleophile and a leaving group of high electronegativity.When silicon is the central atom neither invocation of orbitals nor pseudorotation in the transition state is required to account for the significant retention of configuration that is observed with cyclic silicon compounds if they are not too strained.In the gas phase where SN2reaction rate constants span ca three powers of ten in contrast to proton transfers it has been shown that alkoxides and fluoride are still poor leaving groups.’ Although alkoxides will displace halides from saturated carbon as will halide displace halide alkoxide will not displace alkoxide in the thermoneutral reactions. Indeed alkoxides are relatively poor nucleophiles in the gas phase. The poor leaving-group ability of alkoxides has traditionally been ascribed to their high basicity as most displacements would be endothermic. Low nucleofugicity of fluoride persists in the gas phase and is considered an intrinsic property not a question of solvation or thermodynamics. ’ A. J. Kirby Chem. Br. 1980 16 36. W. P. Jenks Acc.Chem. Res. 1980 13 161. E. Haslam Tetrahedron 1980,36 2409. A F.Effenberger Angew. Chem. Int. Ed. Engl. 1980,19,151. ’ R. M. Magid Tetrahedron 1980 36 1901. J.-P. Begue and M. Charpentier-Morize Acc. Chem. Res. 1980 13 207. Nguyen Trong Anh and C. Minot J. Am. Chem. SOC. 1980,102,103. ’M.J. Pellerite and J. 1. Brauman J. Am. Chem. SOC. 1980 102 5993. 37 D. G. Morris The a effect i.e. the enhanced nucleophilicity of a reagent with at least one pair of unshared electrons adjacent to the nucleophilic centre generally decreases according as to whether the carbon being attacked is sp- sp2- or sp'-hybridized. For methyl aryl sulphates in MeOH at 25"C the ratio of second-order rate constants for hydrazine and glycine ethyl ester which have comparable basicities is 5.21.9This value increases as the leaving group becomes poorer in accord with an interpretation indicating a larger interaction between nucleophile and sp3- hybridized carbon in the transition state and as dictated by the reactivity-selectivity principle.Rate enhancement via a major elevation of the ground state of the a-enhanced nucleophiles is not considered to be of major importance; rather the enhanced reactivity resides in the antibonding HOMO of inhomogeneous polariza- bility and donation of these electrons to the reaction centre lowers the energy as reaction proceeds. The same effect termed supernucleophilicity has been considered by MO theory and related to the number of valence electrons and a atoms associated with the reactive centre.lo There is ambivalence in the case of three-co-ordinate entities since NC13 is only weakly nucleophilic whereas the sulphite ion S032- is a known supernucleophile. For the substrates MeTh' (1-methylthiophenium ion) MeOC103 and MeOTf (Tf = triflate) the rate-constant ratio kH20/kD;0 approximates to unity for nucleophilic attack by water at the methyl carbon when water is in dilute solution in a dipolar aprotic solvent e.g. acetonitrile or sulpholane." Water is monomeric in MeCN at concentrations of less than 0.1mol l-l in which concentration range MeTh' is mainly unhydrated. In H20 or D20 the ratio of pseudo-first-order rate constants k:/k is 1.128at 25 "C. The solvent isotope effect arisesfrom differences in the rotational relaxation times for liquid H20 and D20.Rate constants kI and koTs have been measured for the reaction of Me1 and MeOTs with a number of transition-metal nucleophiles.12 Values of kI embrace more than eleven powers of ten from 2.8 X lo6for [CpFe(C0)I2- in THF at 25 "C to 3.6 x lo-' 1mo1-ls-l for [RhCl(CO)(PPh3)2] in MeI at 25 "C; the rate-constant ratio kI/kOTsvaries from lo8for [Co(CN),I3- to for [LiCuMe2I2. The first evidence for an intermediate S,2 mechanism has been claimed by the Casadevalls' group,13 in an examination of the solvolysis of (1) in hexafluoroisopropyl alcohol and trifluoroacetic acid. Solvolysis of secondary tosy- lates take place in CF,C02H and 9'7% aqueous (CF3)2CHOH without solvent assistance; such is the case for 2-adamantyl tosylate (2-AdOTs) in all solvents.For (l),the ratio ks/ kc [as defined in equation (l)]with X = Bu'OH is 64; values greater E. Buncel C. Chuaqui and H. Wilson J. Org. Chem. 1980,45 3621. lo W. B. England P. Kovacic S. M. Hanrahan and M. B. Jones J. Org. Chem. 1980,45 2057 J. L. Kurzand J. Lee J. Am. Chem. SOC.,1980,102,5428. l2 R.G.Pearson and P. E. Figdore J. Am. Chem. SOC.,1980 102 1541. l3 J. Laureillard A. Casadevall and E. Casadevall Tetrahedron Lett. 1980 21 1731. Reaction Mechanisms -Part (ii) Polar Reactions 39 than 10correspond to solvent assistance. A distinction between an SN2-intermediate mechanism rather than the classical sN2 counterpart is made on the basis of product analysis. Thus 63% of olefin (2) is formed which together with at least a part of the 33% of olefin (3) arises from cation-mediated cis -elimination.The intermediate ion-pair if 'nucleophilically solvated' would carry a significant positive charge on the reactive carbon. The /3 axial group serves to hinder approach of the solvent. It is also noted that weak nucleophilic assistance can bring about large rate effects. ks [kt(ROTs)/k,(2-AdOTs)]{in solvent X} -= CF3C02H [or (CF3)2CHOH]} (1) kc [kt(ROTs)/k,(2-AdOTs)]{in The reaction of 2,4,6-triphenylpyridinium ions e.g. (4) with for example piperidine results in transfer of the benzyl substituent as indicated in Scheme 1.14 From a kinetic analysis of the reaction of (5) the authors concluded that reaction takes place via unimolecular and bimolecular mechanisms which are independent and provide no evidence for an intermediate mechanism.Ph Ph R R (4) R=CH2Ph (5) R=Pr' Scheme 1 The special salt effect that is usually manifested by dramatically increased polarimetric rate constants at low concentrations of added LiClO during acetolyses of diverse tosylates has been shown for the first time to affect the nature of the pr~ducts.'~ Thus during acetolysis of optically active (6),the phenyl-assisted (kA) route accounts for 30% of the reaction pathway in the absence of LiClO,. Addition of 0.02M-LiC10 causes an increase in retained acetate to ca 48% on account of stabilization of the cation as depicted in (7). PhCHzCHMe 1 -0Ts OTs H-OS (6) (7) Analysis of crystal structure parameters of S-methylmethionine chloride hydro- chloride (8) shows that the 0 --C distance is 2.97 % and the S-C...O angle is 143"; in basic solution homoserine lactone (9) is readily formed from S-methyl- methionine.16 The relatively short C..-0contact is regarded as an incipient stage of an exocyclic nucleophilic displacement. 14 A. R. Katritzky G. Musumarra K. Sakizadeh S. M. M. El-Shafie and B. Jovanovic Tetrahedron Lett. 1980,21,2697. L. S. Miller D. Zazzaron J. J. Dannenberg R. Metras and M. Gillard J. Org. Chem. 1980 45 641. l6 D. Britton and J. D. Dunitz Helv. Chim. Actu 1980 63 1068. D. G. Morris The stereochemistry of replacement at the y-carbon of 0-succinylhomoserine (10)during conversion into cystathionine (12) by cystathionine y-synthetase occurs with retention of configuration at the y-carbon (C-4).l7 The reaction is mediated by syn-elimination of P-HR and y-0-succinyl to give (11).c0,-(10) A diminution in rate constant of 3.5 x lo3has been found for an a-cyano-group from consideration of solvolyses of 2-propyl sulphonates." This value arises since the a-cyano-group though inductively strongly destabilizing toward formation of a carbo-cation can provide a countervailing mesomeric stabilization. A P-cyano substituent is capable of causing a rate retardation of lo4-10'; here the possibility of mesomeric stabilization of positive charge is denied to the cyano-group. The mesomeric effect of the cyano-group in a position a to a positive charge is significantly diminished when charge delocalization is extensive in the transition stage for ionization while the inductive effect remains strong.Thus the value obtained for the relative rate constants kH/kCNfor (13) and (14) is ca lo6 and represents a minimal value for the inductive effect of an a-cyano substituent in an ionization reaction. NC OTs CF3IAr-C-OTs I CH3 (13) (14) (15) The solvolyses of substrates such as (15) have been executed in 80% aqueous ethanol in which there is insignificant solvent participation." The compound (15; Ar=Ph) is even less reactive than benzyl tosylate. When Ar in (15) has activating substituents a plot of the logarithm of the relative rate constants versus (T+ gives a slope p+ = -8.82 that is the most negative solvolytic value hitherto recorded and which is indicative of intense electron demand at the reaction centre.l7 M. N. T. Chang and C. Walsh J. Am. Chem. SOC.,1980,102,7368. P. G. Gassmann and J. J. Talley J. Am. Chem. Soc. 1980,102 1214. l9 K-T. Liu and C-F.Sheu Tetrahedron Lett. 1980 21 4091. Reaction Mechanisms -Part (ii)Polar Reactions A highly stereoselective though not apparently stereospecific route to secondary alkyl bromides has been described,20 and it is outlined in Scheme 2. Stereoselec- tivities in excess of 90% are cited. R2. i or ii RZ iv R2 ,qOH -PhSe RH Reagents i PhSeCN Bu,P; ii MeS0,Cl; iii PhSeNa; iv Br, NEt Scheme 2 A mechanistic bifurcation has been reported from the reaction of the selenonium ion (16).With potassium t-butoxide a mixture of selenides (17) and (18) together with methyl and benzyl t-butyl ethers was formed; these products arise from attack on the selonium salts rather than iodides.’l However with sodium hydride in liquid ammonia appreciable quantities of the product of [2,3] sigmatropic rearrangement were observed consequent upon the formation of the ylide (19) from (16) and (16) (19) The enzyme-catalysed cyclization of specifically labelled copalyl pyrophosphate (20) a frequently encountered step in the biogenesis of (inter alia) ent- sandarocopimaradiene has been investigated during incubation of (9-[1-2H1]-geranylgeranyl pyrophosphate precursor.22 The incubation produced (E)-[16-2Hr]-ent-sandarocopimaradiene(21)as a consequence of SN’cyclization occurring with anti stereochemistry.Examples of both syn and anti SN’cyclizations have been reported. ‘H 2H ‘H A stereoelectronic effect which finds analogy in the anomeric effect of acetals has been proposedz3 from the reaction of iodide ion with cyclic dioxenium salts e.g. (22) which are planar and which exist in the (2)form shown. From (22) 29% of lactone (23) together with an unexpected product the iodo-ester (24) are formed. In the pathway indicated in (22) the C-5-0-2 bond that is being broken is anti-periplanar to the c-1-0-1bond; thus the electron pair of the c-5-0-2 bond can be delocalized via interaction with a T* antibonding orbital of the C-1-0-1 polar bond. Such an energy-lowering interaction is denied to the lactone pathway where by contrast the bond being broken is anti-periplanar to the C-1-C-2 bond.2o M. Sevrin and A. Krief J. Chem. SOC.,Chem. Commun. 1980 656. 21 P. G. Gassrnann T. Miura and A. Mossrnan J. Chem. SOC.,Chem. Commun. 1980 558. 22 K.A. Drengler and R. M. Coates J. Chem. SOC.,Chem. Commun. 1980,856. 23 N.Beaulieu and P. Deslongchamps Can. J. Chem. 1980,58 164. D. G.Morris 3 Carbo-cations The norbornyl cation and its derivatives continue to provide good copy and two novel experiments concerned with this ion have been described recently. A calorimetric determination of the heat of isomerization of the 4-methyl to the 2-methyl 2-norbornyl cation [(25) -+(26)] in S02C1F-SbF5 has been madez4 and compared with the heat of isomerization of the s-butyl to the t-butyl cation.No neutral molecules are involved in the comparison(s); in general contributions of the initial state to the free-energy diagram can bedevil attempts to interpret rates of solvolysis or heats of ionization. At -100 "C both of the carbo-cations (25) and (26) can be generated from the respective chlorides whereas at -55 "C the chlorides are immediately converted into the 2-methylnorbornyl cation (26). For the secondary chloride the heat of isomerization of (25) to (26) is the difference between the heat of ionization at -100 "C and that at -55 "C. A value of 6.57*0.41 kcal mol-' was found as compared with a 'normal' value of 14.20 f0.6 kcal mol-1 for the isomeriz- ation of s-butyl to t-butyl cation. The difference between these values i.e. 7.5 kcal mol-' has been ascribed to the special stabilizing feature enjoyed by secondary norbornyl cations in the 'most compelling piece of evidence yet pre~ented'.~~ Substitution by deuterium perturbs the functional symmetry that is brought about by rapid degenerate rearrangement in a carbo-cation.Thus perturbation occurs in the averaging of the I3C n.m.r. absorptions of those carbons which are interchanged by rearrangement such that large splittings are observed in the averaged resonances. At -150 "C an upper limit of 2.3 p.p.m. is put on isotope splitting for (27) (shown as a classical ion for convenience) since for C-1 and C-2 WIl2=2.3 p.p.m.; peak areas show that deuterium is not scrambled. A static symmetrical structure is consistent with the n.m.r. evidence which is not in accord with a rapidly equilibrating species.25 As a control to allow the validity of the method to be assessed the absorptions of C-1 and of C-2 in (28) which exists as a rapidly equilibrating pair of cations show a splitting of 105 p.p.m.at -130 "C whereas C-1 and C-3 are split by only 0.33 p.p.m. in (29). Interestingly in the 1,2-dimethylnorbornyl cation (30) which is taken to be partially delocalized a corresponding splitting of intermediate value (23.9 p.p.m.) is obtained. 24 E. M. Arnett N. Pienta and C. Petro J. Am. Chem. SOC.,1980 102 398. *' M. Saunders and M. R. Kates J. Am. Chem. Soc. 1980 102,6867. Reaction Mechanisms -Part (ii) Polar Reactions The rate of solvolysis of (31) is 3.5~10~ times faster than that of t-butyl p-nitrobenzoate in 80% aqueous dioxan thus making it the most reactive saturated tertiary derivative known to date.26 The products are unrearranged alcohol and olefin.The high solvolysis rate has been attributed to relief of severe non-bonded interactions between the inner protons of the ethano bridges. This endo-side congestion of (3 1)is diminished in the benzo-fused analogue (32) which accordingly solvolyses less frenetically. Thermodynamic and spectroscopic properties of 2-bicyclo[2.1. llhexyl cations are intermediate between those of 2-norbornyl and cyclopentyl cations; thus the difference in free energy between ions (33) and (34) is 7.0-9.8 kcal mol-' as compared with values of 5.5 and 12 kcal mol-' respectively for norbornyl and cyclopentyl analog~es.~' The I3C chemical shifts for the positively charged carbons indicate an intermediate degree of charge delocalization for (33) [S(C') = 322.01 2-methylnorbornyl cation [270.2] and methylcyclopentyl cation [336.7 p.p.m.1 with the proviso that the correlations hold between chemical shift and charge density.An unsymmetrically bridged ion (35) has been proposed in which the distance C-1-C-6 >C-2-C-6. Further bond shifts are considered to be a requisite of the symmetrical n.m.r. spectrum; thus the ion must undergo a very rapid shift of C-2-C-6 -+ C-2-C-5 and a degenerate Wagner-Meerwein shift that interchanges the bonds C-1-C-6 and C-2-C-6. (33) (34) (35) In their investigations on deuterium isotope effects on carbo-cations Saunders and Kate~~~ concluded that the bicyclo[2.1.llhexyl cation had a static bridged structure on account of a deuterium-induced splitting of 1.18 p.p.m. between C-1 and C-2 at -150 "C and that the cation should be represented as (36). Formolysis of specifically labelled cyclopent-3-enyl tosylate proceeds with >99'/0 retention of configuration as the result of participation of the double-bond to the exclusion of any competitive participation by the solvent.*' This r-participation in the ionization process has not been picked up in previous studies of products or 26 L. A. Paquette K. Ohkata and R. V. C. Carr J. Am. Chem. Soc. 1980,102,3303. 27 L. R. SchmitzandT. S. Sorensen J. Am. Chem. SOC.,1980,102,1645. 28 J. B.Lambert R. B. Finzel and C. A. Belec J.Am.Chem. Suc. 1980,102 3821. D. G. Morris rates; the stereochemical analysis is thus more sensitive rate enhancements not being obligatory for participation. The tricyclopropylcyclopropenium ion (37) has been prepared and is one of the most stable hydrocarbon cations known presumably on account of a bisected conf~rmation.~~ Potentiometric titration in 50% aqueous MeCN indicated a pKR+ value of 1O.Ok 0.3; a-conjugation with cyclopropyl groups is thus more effective than wconjugation with phenyl groups or the inductive effect of alkyl groups in stabilizing the cyclopropenium ior,. A series of 2,5-diaryl-2,5-norbornyldications (38) has been prepared; their remarkable stability is achieved through charge dispersal into the aryl rings thereby decreasing charge-charge The positively charged carbons C-2 and C-5 are shielded by ca 15p.p.m.from the corresponding carbon in the monocation. A plot of S(C-1) vs. S(C-3) is linear in the dications (38) indicating a similar response at these carbons to change in the substituent on the aromatic ring. Such is not the case in 2-aryl-2-norbornyl cations where departure from linearity is observed for electron-withdrawing substituents; this is in accord with the incursion of non-classical delocalization since the aromatic ring is now less able to stabilize positive charge. Diprotonation of the 1,6-methano-[ lO]annulene system (39) with magic acid leads to formation of the stable dication (40) in which two allylic cations are bound to the same carbon of a cyclopropane ring.31 A preference exists for (40) over (41) [from which (40) (with its C,symmetry) can be readily distinguished] on account of the cyclopropane-enhanced homoconjugation between the two allylic cationic centres in (40) the conjugation between the allylic cation centres in (41)being very poor.(39) (40) (41) 2-Adamantyl ONN-azoxytoluene-p-sulphonate(42) has been prepared and the activation parameters have been determined from solvolysis in a number of solvents e.g. aqueous triflu~roethanol.~’ Parameters in accord with S,l reactions were observed and the authors claim that a deaminative fragmentation is for the first time amenable to kinetic analysis. The products are alcohols and ethers of un-rearranged structure. 29 K. Komatzu I.Tomioke and K. Okamoto Tetrahedron Lett. 1980 21 947. 30 G. A. Olah G. K. S. Prakash andT. N. Rawdah J. Am. Chem. SOC.,1980,102,6127. 31 K. Lammertsma and H. Cerfontain J. Am. Chem. Soc. 1980 102 3257. 32 H. Maskill P. Murray-Rust J. T. Thompson and A. A. Wilson J. Chem. Soc. Chem. Commun. 1980 788. Reaction Mechanisms -Part (ii) Polar Reactions 4 Carbanions Ab initio MO calculations of XCH2- in which X was Li BeH BH2 CH3 NH2 OH and F have been carried out. The ion H2C=BH2- is calculated to have a planar structure in its most stable form with a very short (1.44A)carbon-boron bond. Also CH2Li- is indicated to have a planar C2"structure (43),which is stabilized with respect to CH3- the stabilization being provided (rather unexpectedly) by an alkali metal of low electronegativity and this has been attributed to the p-orbitals on The p-orbitals of sodium are of much higher energy than those of lithium and accordingly the ion CH2Na- is massively destabilized (by cu 100kcal mol-') with respect to CH3-.Both CH2Na-.and CH2F- have been calculated to be pyramidal and in the latter case the withdrawal of a-electrons by the electronegative fluorine and four-electron 7-destabilization are in opposition; the importance of the withdrawal of cr-electrons is manifest in the stabilization energy which is the largest for electronegative substituents. Protons can be abstracted from Bu'NO and Bu'CHO in the gas phase with unexpected ease.34 The (M-H)- ions of Bu'NO and Bu'CHO are stabilized by 25-37 kcal mol-' with respect to that derived from methane (AHacid = 416kcal mol-').The gas-phase acidities of Bu'NO and Bu'CHO are intermediate between those of water and methanol. The authors attribute a large part of the stabilization of the anion derived from 2,2-dimethylpropionaldehydeto interaction between the charge in an sp3-hybridized orbital and the dipole moment of the carbonyl group (44).Polarizability and hyperconjugation effects may also contribute to the stabilization energy; homoconjugation may occur but this could lead to cyclopropoxide anions. However this isomerization (if occurring at all) must on the basis of 'H-'H exchange experiments be very slow. H. ,C\ 'c /c=o / Q H/ H (44) 7-Phenylnorbornyl carbanions with Li K (and Cs) as counter-ions have been prepared in [2H8]THF.35Carbon-13 chemical shifts for C-7 and the pura carbon differ by 30 p.p.m.according as to whether Li'or K' is the counter-ion. The authors consider that the 7-phenylnorbornyl anion is intrinsically planar but that when the anion is co-ordinated to the strongly polarizing lithium cation the Coulombic stabilization increases electron localization at C-7. Thus a tetraco-ordinate carbon 33 T. Clark H. Korner and P. von R. Schleyer Tetrahedron Lett. 1980,21,743. 34 A. J. Noest and N. M. M.Nibbering J. Am. Chem. SOC.,1980,102,6427. " P. R. Peoples and J. B. Grutzner J. Am. Chem. SOC.,1980,102,4709. 46 D. G. Morris is formed yielding a pyramidal organolithium compound that is capable of inversion the rate-determining step of which is ionic dissociation with a magnitude AG&s = 9.4*0.2 kcal mol-'.The 13Cn.m.r. spectra of the K and Cs salts show little temperature variation and are consistent with a symmetrical planar benzylic carbanion. Consideration of other literature together with these results indicates that a simple carbanion e.g. CH3- has an inversion barrier of <5 kcal mol-'. By means of cyclic and second-harmonic a.c. voltammetry the electrochemical oxidation potentials have been determined for a series of organolithium compounds in HMPA;36 from these data the bond-dissociation energies and the pKa values of Ph3CH (the ion-pair acidity) are estimable. The authors claim that the electro- chemical thermodynamic method where applicable is probably the most re-liable way for estimation of pKa values of very weak acids.The ally1 anion [pKa(R-H) =47.1-48.01 is reasonably more basic than the benzyl anion [pKa(R-H) =44.2-45.41. Corresponding values of 44.2-45.4 were found for t-butylpropargyl anion (though this value may need modification on account of overpotential) and 22.2-23.4 for cyclopentadienyl anion. The latter value is not unreasonable for the solvent THF with'30'h v/v HMPA though rather higher than the figure of 16 that was obtained in water. A rather stronger acid 5H-perfluoropentamethylcyclopentadiene (45),has been prepared by Lemal's group.37 In water this compound is readily soluble to give the anion (46);this is reprotonated in concentratedH2S04. The PKa of (45)is 4 -2; thus (45) is the strongest acid without conjugating substituents and the introduction of five CF groups is responsible for an acidity increase of at least 18 orders of magnitude.However this consistent acidifying effect of CF is not mirrored by fluorine which stabilizes CH3- (pKa of CF3H is 30.5) while destabilizing by means of electron repulsion the anions of lower energy that are derived from fluorene or nitro-alkanes. Me Me F3C I I o=s s=o I I .-_* F3Cp$ H CF3 CF3 CF3 Me-C-H H-C-Me F3:y:F3 Ph Ph I I (45) A white precipitate was obtained by cooling a solution of the lithiated carbanion from racemic PhCH2S(0)Me in THF to -100°C. After work-up this solid was dispersed at 25 "C and a mixture of nitrogen and methyl iodide was passed over it to give a single diastereoisomer [(R,S)and (S,R),38 (47a) and (47b)l.In the presence of chelating agents such as D20 and ethanol only slight stereoselectivity was retained. Members of a new class of reactive intermediates a-keto-dianions have been prepared. Their formation follows the reaction of lithium enolates of primary or secondary a-bromo-ketones e.g. (48) with t-butyl-lithium to give (49) in which the lithium may well be covalently Consistent with the assigned structure 36 B. Jam J. Schwarz and R. Breslow J. Am. Chem. SOC.,1980 102,5741. 37 E.D. Laganis and D. M. Lemal J. Am. Chem. SOC.,1980,102,6633. 38 J. F.Biellmann J. F. Blanzat and J. J. Vicens J. Am. Chem. SOC.,1980 102,2460. 39 C.J. Kowhlski M. L. O'Dowd M. C. Burke and K. W. Fields J.Am. Chem. SOC.,1980 102 5411. Reaction Mechanisms -Part (ii) Polar Reactions (48) (49) (50) quenching with DOAc-D20 gives a dideuterio-ketone. Unique to a-keto-dianions is the silylation on the carbon atom that was originally adjacent to the keto-group e.g. to give (50). Rearrangement of (51)with potassium t-butoxide in HMPA gave (53) via a [l,21 shift of a methyl group in (52).40This rearrangement represents the first example of base-catalysed migration of an alkyl group from a non-heterosubstituted carbon to an adjacent carbonyl carbon atom. The anion of (51)is a novel member of a class of blocked aromatic molecules which can become aromatic by migration of a single substituent. 0 0- 0 (51) (52) (53) 5 Reactivity of Carbonyl Groups Ab initio MO calculations (4-31G) indicate that the reaction €320 + H2C0-P CH2(OH) has EA= 44.1kcal mol-' and is exothermic by 16.8kcal mol-'.A planar four-membered transition state is impli~ated.~~ A second water molecule was introduced (as a token solvent) and the acidic and basic features of the catalyst were combined to give significant energy lowering at C-0 separations of 1.7A with proton transfer and nucleophilic bond formation occurring simultaneously as shown in (54). (54) The reactions of simple nucleophiles e.g. H- OH- or MeO- with formaldehyde have been allowed to take place at ca 0.5 Torr enabling the first observation of stabilized adduct~.~~ Under the reaction conditions energy which appears as internal hbrations of MeO- after addition is removed by collision with the atoms.At 297 K the two-body rate constant for addition of NH2-to H2C0 is (1.9kO.5)~ cm3 molecule-' s-'. Transfer of hydride ion between two carbonyl groups can be affected in opposite ways by the cation and the base depending on whether or not the transition state permits complexation of both oxygen atoms by a single cation.43 The rate of 40 B. Miller and A. K. Bhattacharya J. Am. Chem. SOC.,1980,102 2450. 41 I. H. Williams D. Spangler D. A. Femec G. M. Maggiora and R. L. Schowen J. A.m. Chem. SOC. 1980,102,6619. 42 D. K. Bohme G. I. Mackay and S. D. Tanner J. Am. Chem. SOC.,1980,102,407. 43 E. W. Warnhoff P. Reynolds-Warnhoff and M. Y.H. Wong J. Am. Chem. SOC.,1980,102 5956. 48 D.G.Morris intermolecular hydride transfer from Pr'OM to (53 leading to (56),increases as the Lewis acidity of the cation increases i.e. AI3+> Li' > Ba2' > Na' > K' and thus decreases with increasing basicity of the medium; this is in accord with the presence of a cyclic transition state. Concurrently the rate of intramolecular transfer of hydride increases in essentially the reverse order as is also the case for acyclic ketones which are mediated by an ionic transition state (58). The reversal of order is a function of how the oxygens are incorporated into the transition state for hydride transfer. A cyclic transition state (57) either intra- or inter-molecular will be favoured by the better Lewis acid. However hydride transfer is preferred by greater negative charge on oxygen i.e.by the poorer Lewis acid when as in the intramolecular reaction of (53 a cation-bridged transition state is not possible. .M.. ,li O'' .?/\ Px OH 239. ,,@-\/ c...HJ\ 0P (55) OH HO(56) P (57) (58) The sodium alkoxides derived from the ketols (59)-(61) undergo 1,4 hydride transfer with (61) rearranging lo0.'times faster than (60),which in turn rearranges a102 times faster than (59).44These rate sequences correspond to the separation between carbonyl carbon and migrating hydrogen. (59) n = 1; (60) n = 2 (61) n = 3 Monomeric methyl metaphosphate MeOP02 prepared and then allowed to react in situ with acetophenone gives an enol phosphate via (62),which is formed by direct attack on carbonyl oxygen; in (62) the carbonyl group is now activated for nucleophilic The hydrolysis of phosphate esters including ATP and other high-energy phosphates occurs uia a monomeric metaphosphate or by a kindred mechanism in solution and the idea has been floated that enzyme-catalysed phosphoryl transfers could be mediated by a monomeric metaphosphate or by a related mechanism.This would ascribe a kinetic role to ATP in addition to its better-known thermodynamic properties. One experiment is cited where carbonyl oxygen is transformed into inorganic phosphate during the conversion of C=O into C=N by ATP-dependent amidotransferases. Whereas in competitive experiments the value of AAG* for the reactions of PhCHO and PhCOMe with MeLi is <1 kcal mol-' the reagent (Me2CH0)3TiMe is appreciably more selective with AAG* 'approximately one order of magnitude larger' and the aldehyde being the more reactive.46 A variety of other functionalities e.g.ester epoxide and nitrile are tolerated. 44 G.-A. Craze and I. Watt J. Chem. SOC.,Chem. Commun. 1980 147. 45 A. C. Satterthwait and F. H. Westheimer J. Am. Chem. SOC.,1980 102,4464. 46 B.Weidmann and D. Seebach Helv. Chim. Acta 1980,63 2451. Reaction Mechanisms -Part (ii) Polar Reactions 6 Nucleophilic Addition to Olefins In (63) nucleophilic addition readily takes place to the unactivated do~ble-bond.~' The ready formation of (64) has been attributed to steric compression. Nucleophiles add readily to an olefin that is co-ordinated to a transition-metal centre and electrostatic forces provide only slight activation; the role of the metal acting as electron-attractor and back-donator is ambigu~us.~' Calculations indicate that as the ligand ML is displaced by an amount A [as in (65)] an energy lowering of the LUMO occurs and the LUMO becomes concentrated on the remote carbon C-a.A carbanionic intermediate has been proposed for the first time in the substitution of an activated halogeno-olefin (66) by a non-amine nucleophile; this stereoconver- gence is not the result of prior equilibration of the ~lefin.~' 7 Esters and Carbodi-imides On the basis of orbital-steering postulates the rates of lactonization of (67) and (68) should differ by ca lo4 on account of a difference of 10" in the angle 0-1-C-2-C-3 as calculated by a force-field method.However the relative rate constants for acid-catalysed lactonization were 1:1.2 thereby refuting the above p~stulate.~' The derived lactones showed Av(C0) = 7 cm-' which indicates that there are only slight differences in strain energy and thus renders the substrates valid for comparison. (67) (68) Exceptional micellar stereoselectivity is shown in the cleavage of diastereoisomeric dipeptide esters (69). Solubilization of (69) in (70) gives very large rate enhancements relative to cetyltrimethylammonium chloride together with marked selectivity for cleavage of the ~,~-substrates." Models suggest that 47 R. A. Pfund W. B. Schweizer and C. Granter Helv. Chim. Acta 1980,63,674. 48 0.Eisenstein and R. Hoffrnann J. Am. Chem.SOC.,1980,102,6148. 49 Z. Rappoport and A. Topol J. Am. Chem. SOC.,1980,102,406. F. M. Menger and L. E. Glass J. Am. Chern. SOC.,1980,102 5404. '' R. A. Moss,Y-S. Lee and K. W. Alwis J. Am Chem. Soc. 1980,102,6646. 50 D. G. Morris PhCH2O-C-NH-CH-C-N It I * 0 H C-0002 c1-! 0 n-C16H33Nf(Me)2CH2CH2SH [(Z)-Ala-Pro-PNP] (69) R = Me (70) uniquely for L,L-substrates the methylene chain of (70) fits into the clefts defined by the Pro and PNP moieties and the R group of the variable amino-acids such that the -CH2CH2S-functionality is ideally located behind and above the apposite carbonyl group. This arrangement is also beneficial in that the hydrophobic groups are located in the micellar interior whereas the carbonyl oxygens and the aromatic rings of PNP interact in favourable electrostatic manner with the quaternary nitrogen atom of the surfactant.The rate constant for alkaline hydrolysis of (71) is 5 x lo5 times greater than that for (72) via formation of a lactone which at alkaline pH is further hydr~lysed.~~ From comparison of the intramolecular first-order rate constant of (71) with the intermolecular second-order rate constant for (72) an effective concentration of OH-of ca 5 X lo7moll-' is given as that concentration of OH- which is required for the intermolecular reaction to proceed at the same rate as its intramolecular counterpart. This translates to a corresponding value of ca lo8moll-' for alkoxide and has been ascribed to the large loss of translational and rotational entropy that is associated with those concerted reactions for which there is a negligible contribu- tion from solvation effects.Protonated intermediates HC(OH)2&H3have been considered as models for acid-catalysed decomposition of the tetrahedral intermediate in the hydrolysis of amide~.~~ Protonation leads to lengthening and weakening of the C-N bonds particularly [e.g. see (73)] where the C-N bond is anti-periplanar to two lone pairs. A more muted and opposite effect is indicated for the C-0 bonds. The largest stereoelectronic effect comes from an interaction between a lone pair on oxygen and a cr* orbital of CN'. Base-catalysed hydrolyses have also been con- sidered with less emphatic conclusions. A H Acylation of the water-soluble carbodi-imide (74) shows a Brgnsted slope of -0.67 and embracing a large pK range which is consistent with concerted attack by -0Ac and general acid catalysis (see Scheme 3).54 52 J.J. Morris and M. I. Page J. Chem. SOC.,Perkin Trans. 2 1980 679. '' J. M. Lehn and G. Wipff J. Am. Chem. SOC.,1980,102,1347. 54 I. T. Ibrahim and A. Williams J. Chem. Soc. Chem. Commun. 1980.25. Reaction Mechanisms -Part (ii) Polar Reactions Et\ AcO-C Et AH N N H~A112 It N --* AcO‘+NR EtNH I -* +NHR \ R + (74) R = CH2CH2CH2NMe3 Scheme 3 8 Elimination Reactions The reaction of (75) with -0Bu‘ in Bu‘OH gave exclusively 1-chloroacenaphthylene via an irreversible Elcb mechanism.” The loss of fluoride which is formally the poorer leaving group occurs since the carbanion (76) is much the more stable of the two possibilities.However the difluoro-analogue of (75) probably also reacts via an (Elcb) mechanism. Hno + R2 R’ H\_/Co2-R2 R’ (77) (78) (75) The 3-deprotonated oxetanones (77) are unexpectedly stable to elimination on account of an orthogonal disposition of the relevant orbitals so much so that (77) can be intercepted by ele~trophiles.’~ However elimination does proceed (albeit lethargically) to give acrylic acid anions (78). The primary process in elimination reactions of N-[P-(p-nitrophenylethy1)Iquin-uclidinium ions e.g. of the chloride (79) with aqueous hydroxide ions is proton transfer with little driving force from explusion of the leaving group.57 Although an E2 mechanism cannot be excluded values of p and isotope effects indicate a transition state in which the proton is ca two-thirds removed with the bond to quinuclidine unchanged except for expectations based on the formation of a carb- anion on a P-carbon atom.CI -(79) On treatment with NH2-in liquid ammonia 3-phenylpropyl iodides and bromides underwent p -elimination the chloride a mixture of p-and y-eliminations whereas the fluoride and tosylate underwent y-eliminati~n.~~ The position of tosylate is anomalous in that &elimination was expected. Moreover the strong base was also removing the methyl protons of the group; thus only 20% of phenylcyclopropane 55 E. Baciocchi R. Ruzziconi and G. V. Sebastiani J. Chem. SOC.,Chem. Commun. 1980 807. 56 J. Mulzer and T.Kerkmann J. Am. Chem. SOC., 1980,102,3620. ” S. Alunni and W. P. Jencks J. Am. Chem. SOC.,1980,102,2052. C. L. Bumgardner J. R. Lever and S. T. Purrington J. Org Chem. 1980,45,749. D. G.Morris was formed. Similar treatment of 3-phenylpropyl benzenesulphonate however gave only substitution products. Buffered solvolyses (in 80% aqueous ethanol) of a number of deuteriated norbor- nyl derivatives exemplified by (80) and (81) under El-like conditions gave a stereoselectivity for loss of the endo-proton that is attached to C-6 over loss of its exo-counterpart in the range of 10 1 to 15 :1 in the formation of 7-halogeno- nortricyclenes by 1,3-eliminati0n.~~ A new method has been proposed for distinction between (Elcb) and E2 mechanisms based on a linear free-energy relationship between rates of elimination (k,)and Taft's polar substituent parameter (u"), together with leaving-group ability (L),which is derived from 9-(X-methyl)fluorene as a standard system.60 In equation (2) 1 (the sensitivity of the system to change of leaving group) monitors a change in mechanism insofar as 1 measures the slope of data that are treated graphically when an Elcb mechanism holds and the incursion of an E2 pathway is manifest in curvature in the graph that may be drawn.log(k,/k,0) =p*a" +1L (2) 59 N. H. Werstiuk F. P. Cappelli and G. Timmins Can. J. Chem. 1980 58 2093. 6o A. Thibblin Chern. Scr. 1980,15 121.