3 Reaction mechanisms Part (ii) Polar reactions By IAN W. ASHWORTH Zeneca Ltd. Process Studies Group Huddersfield Works Leeds Road Huddersfield UK HD2 1FF 1 Introduction The experimental study of reactive intermediates has continued to be of considerable interest due to the relatively facile generation of previously inaccessible species by laser flash photolytic (LFP) techniques. The application of this methodology to the generation and study of carbenium and nitrenium ions,1 ynols and ynamines2 and carboxylic acid enols3 has been reviewed. 2 Solvolysis and carbocations Studies of the reactions of a range of solvolytically generated a-substituted 1-(4- methoxyphenyl)ethyl carbocations 1 in 50 50 (v/v) MeOH–H 2 O have shown that a thioamide substituent strongly favours deprotonation to form an alkene over nucleophilic addition.4 Experimental and computational results are consistent with the conclusion that the partitioning of the carbocationic intermediate between substitution and elimination products is strongly controlled by their relative stabilities.The a-(N,N-dimethylaminothioformyl)-4-methoxybenzyl carbocation 2 has been found5 to undergo cyclisation to give the benzothiophene 3 which traps 2 with an e¶ciency comparable to an azide to yield the adduct 4. + + 1 2 3 4 R OMe Me2N S OMe S NMe2 OMe S NMe2 Ar Me2N S OMe The solvolyses of the E and Z isomers of a number of substituted hydroximoyl chlorides 5 have been studied.6 A positive *S8 and Hammett o of[1.4 were taken as Royal Society of Chemistry–Annual Reports–Book B 43 evidence of a dissociative mechanism proceeding via a nitrilium ion intermediate 6.The large di§erence in the rates of the reaction of the E and Z isomers was ascribed to a stereoelectronic e§ect. Studies of the e§ect of solvent upon the rates of solvolysis of the benzhydryldimethylsulfonium ion 7 have shown that the dependence of rate upon solvent composition may be described by an extended form of the Grunwald–Winstein equation utilising Y` and aromatic ring parameter (I) values.7 An S N 1 mechanism was proposed based on this correlation the observation of common molecule return and product selectivities in ethanol–water mixtures. A modified Grunwald–Winstein treatment has also been applied to the solvolyses of a range of (1-arylcycloalkyl)methyl toluene-p-sulfonates 8 and 9,8 where anchimeric assistance by the aryl group in the solvolysis was shown to be pronounced in the [1-(p-methoxyphenyl)cyclobutyl]- methyl toluene-p-sulfonate.n 5 6 7 8 n = 1 9 n = 2 Cl Ar N OMe Ar C N+ OMe Ph Ph S+ Ar OTs Arylcyclopropylcarbenium ions 10 were generated as transient species by LFP in 2,2,2-trifluoroethanol (TFE) and the kinetics of their reaction with methanol was studied.9 Comparison of the rates of reaction with those of the corresponding arylphenylcarbenium ions generated under similar conditions show the phenyl and cylcopropyl groups to have similar cation stabilising abilities. Lew et al.10 generated and characterised the zwitterionic 9-carboxylatoflouren-9-yl cation 11 flash photolytically in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP). Under acidic conditions the conjugate acid could be observed leading to an estimated pK! of 2 for the carboxylic acid group in HFIP.Generation of the 9-(N,N-dimethylaminothioformyl)fluoren-9-yl cation 12 under stable ion conditions facilitated its spectroscopic investigation.11 The same cation was also generated by LFP of the appropriate chloride precursor in TFE and its quenching with a range of nucleophiles was studied,11 resulting in the same conclusion reached by Richard et al.4 that the N,N-dimethylaminoformyl group stabilises the adjacent cationic centre relative to the methoxycarbonyl and unsubstituted cations. + + + 10 11 12 H Ar CO2 – Me2N S 3 Nucleophilic substitution The competition between electron transfer and bimolecular substitution pathways in nucleophilic substitution reactions has been reviewed by Speiser.12 Studies of the 44 IanW.Ashworth Scheme 1 Scheme 2 Nuc H+ Products HN R N+ O O– R N N+ OH O– R N N+ OH2 + O– Scheme 3 antihydrophobic cosolvent e§ect on the reactions of phenoxides and N-methylaniline with sodium (4-chloromethyl)benzoate 1313 suggested two di§erent geometries for the S N 2 displacement. N-Methylaniline was postulated to react with 13 via a p in-plane approach (Scheme 1) whilst the phenoxide ion reacts with13 in a direct displacement reaction (Scheme 2). Switching to the 2,6-dimethylphenoxide ion as the nucleophile led to an antihydrophobic cosolvent e§ect consistent with a change to an in-plane approach. Interestingly thiophenoxide and 2,6-dimethylthiophenoxide ions showed anomalous reactivity in the presence of added cosolvent which was interpreted in terms of a single electron transfer (SET) mechanism.Investigations of the acid catalysed decomposition of N-nitroamines in concentrated sulfuric acid using the Cox–Yates excess acidity scale showed that the free carbocations were not formed.14 A mechanism was proposed (Scheme 3) in which the aci-nitro tautomer undergoes protonation followed by S N 2 displacement by water at less than 82% sulfuric acid in water and by bisulfate at higher concentrations of acid. Incoming group 11C/14C kinetic isotope e§ects have been successfully measured for the S N 2 reaction between benzyl chloride and the labelled cyanide ion.15 The e§ects of changing para substituents upon these isotope e§ects suggest that electron withdrawing groups have little e§ect upon nucleophile–carbon distance in the transition state. An interesting intermolecular B A-2 aminolysis reaction was observed in the solid state for the binaphthyl derivative 14.16 It was found by X-ray crystallographic analysis of the racemic compound that the amino and ester groups had the wrong orientation for 45 Reaction mechanisms Part (ii) Polar reactions 18 X=H 3-Cl MeO– rds N H Ph CN X –N Ph CN X N Ph X Scheme 4 an intramolecular reaction to occur; however a second molecule within the crystal was found to be su¶ciently close that reaction could take place between the amino and ester functions of neighbouring molecules.4 Elimination reactions An elimination pathway has been found for the aminolysis of N-arylmethyl- 15 and N-aryl-sulfamate 16 esters in chloroform and acetonitrile.17 An E2 process has been postulated on the basis of b-' o!#:- and *S8 values which imply a bimolecular reaction with a strong dependence upon the electron withdrawing ability at nitrogen and the leaving group ability of the ester.Further evidence was provided by studies of the 4-nitrophenylN,N-dimethylsulfamate ester which failed to react under the experimental conditions. The aqueous hydrolysis of 2,4-dinitrophenyl esters of 4-hydroxy-Xbenzenesulfonic acid was found to be independent of pH reaction above the pK! of the hydroxy function.18 The rate of this reaction was found to correlate with the pK! of the substituted phenol and the redox equilibrium constants for the substituted quinone analogues of the postulated intermediate 17 which was taken as evidence of an E1 pathway. 17 16 15 14 NH2 OH CO2Me N H SO2OAr X N H SO2 OAr X O R2 R1 SO2 Elimination of HCl from N-chloramines to form imines has been studied19 and evidence was found which suggests a concerted bimolecular elimination mechanism.The susceptibility of the reaction rate to substituents on the a-carbon was taken as being indicative of an asynchronous mechanism in which deprotonation lags behind leaving group departure. In contrast the formation of an imine in the methoxide promoted elimination of cyanide ion from 18 has been concluded to proceed via an (E1cB) R mechanism (Scheme 4),20 as evidenced by H/D exchange at N and a negative value for *S8. 46 IanW. Ashworth An interesting alkyne forming elimination was observed in place of vinylic substitution in the reaction of the b-halocinnamate 19 with a range of nucleophiles.21 The overall reaction is a dechloromethoxylcarbonylation which is thought to occur by attack of the nucleophile upon the ester carbonyl followed by either concerted elimination of the CO 2 Me group and chloride or the formation of a vinyl anion.Failure of the substitution pathway was attributed to steric hindrance by the bulky aryl group at Cb. 19 Br Cl CO2Me 5 Addition reactions Electrophilic addition to the hindered double bond of anti-sesquinorbornene 20 has been shown to give rise to the products of cis addition to the double bond.22,23 The acid catalysed hydration22 occurs by a mechanism involving rate limiting protonation which may or may not be synchronous with the trapping of the developing carbocation. Bromination in methanol gives the expected products in a ratio which is independent of the [Br~],23 implying that the products arise from ion pair collapse and not from a solvent equilibrated ion pair.The e§ect of a b-silyl substituent on the rate of protonation of a number of alkynes and alkenes in concentrated perchloric acid solutions was investigated by Gabelica and Kresge.24 This study showed a marked rate enhancement by the b-silyl group of the rates of C-protonation and a dependence of the magnitude of this e§ect upon geometry. The nucleophilic addition of hydride from cyanoborohydride to the heteroaromatic rings of the pyrylium and thiopyrylium cations 21 and 22 with loss of aromaticity has been investigated.25 The ratios of 1,2- and 1,4-addition products are comparable to those for the reactions of the same cations (Y\H) with amine and alkoxide nucleophiles.Consideration of the activation parameters and substituent e§ects upon the cyanoborohydride reductions led to the conclusion that they were not initiated by an electron transfer process. Investigations of the activation parameters for the reactions of the C––Si bond of 1,1-diphenylsilene (Ph 2 Si––CH 2 ) with nucleophiles have provided further evidence of a mechanism involving reversible nucleophilic attack at Si followed by rate limiting 47 Reaction mechanisms Part (ii) Polar reactions protonation of the anion formed.26 The rates of reaction of tetramesityldisilene with a range of substituted phenols were studied27 and a concave Hammett plot was obtained the minimum occurring at X\H. This was taken as evidence of a change in mechanism from a rate limiting nucleophilic step in the case of electron donating substituents to a rate limiting electrophilic step in the case of electron withdrawing substituents.6 Carbonyl derivatives Intramolecular participation by a carbonyl hydrate was found in the hydrolysis of the esters 23 and 24.28 The activation parameters substituent e§ects and relative rates of hydrolysis were taken as evidence of a mechanism involving rate limiting addition of hydroxide to the keto-carbonyl which then participated in the hydrolysis of the ester. The rate and equilibrium constants for the aldol addition and elimination steps in a range of intramolecular condensation reactions were determined by Guthrie and Guo.29 Analysis of the experimental results in terms of Marcus theory led to the conclusion that the intrinsic barriers for the intramolecular reactions were similar to those for the corresponding intermolecular processes.24 R=H Me 23 R=H Me Ar O CO2Me R R R R Ar O CO2Me Intramolecular general acid catalysis of acetal hydrolysis has been demonstrated in two model systems containing alkyl acetals. The racemic trans-cyclohexane-1,2-diyl acetal 25 has a complex pH rate profile which suggests that the oxo-carbenium ion intermediate is trapped by the carboxylate anion to form 26.30 The ortho-carboxylic group enhances the rate of reaction by a factor of 220 relative to the corresponding para substituted compounds and a solvent deuterium isotope supporting a mechanism involving general acid catalysis was obtained. Brown and Kirby31 found the benzaldehyde acetal 27 to be highly reactive towards intramolecular general acid catalysed hydrolysis.An e§ective molarity of 2800 was estimated as the appropriate reference reaction was too slow to be observed. This highly e¶cient general acid catalysis was ascribed to the development of a strong intramolecular hydrogen bond. 27 26 25 O O OH O O O O OH O O H O OMe Ph 48 IanW. Ashworth The study of the enolisation of carboxylic acids esters and amides has been pursued by a number of groups. Amyes and Richard32 used NMR spectroscopy to study the exchange of deuterium into ethyl acetate catalysed by a range of 3-substituted quinuclidine bases and obtained a pK! K of 25.6 for ethyl acetate acting as a carbon acid. The enolisation of malonic acid and its mono methyl ester were studied by Eberlin and Williams,33 who obtained values of 8.13 and 8.84 respectively for pK! K.The complex dependence of the kinetics of bromination of malonic acid between pH 1 and 4.3 upon the concentration of the carbon acid was explained in terms of three di§erent mechanisms. LFP techniques have been used to generate ditipylketene (tipyl\2,4,6-triisopropylphenyl) which upon reaction with dimethylamine gave a stable amide enol 28 which could be studied spectroscopically.34 A similar approach yielded the corresponding carboxylic acid enol 29 upon hydration of the ketene intermediate.35 Kresge and co-workers36 generated the enol of acetoacetic acid by the hydration of acetylketene and studied the e§ect of pH upon the rates of ketonisation. Their findings were discussed in terms of the ionisation state of the enol alcohol and carboxylic acid. 29 28 Tip Tip OH NMe2 Tip Tip OH OH 7 Reactive intermediates The basicity of aryl nitrenes was studied by following their flash photolytic generation from the appropriate azide and subsequent protonation to form an aryl nitrenium ion.37 In the case of phenylnitrene 1M acid was required to obtain appreciable amounts of the nitrenium ion by protonation which occurred in competition with ring expansion.Biphenyl-4-yl- and fluoren-2-yl-nitrene were found to undergo side reactions less rapidly leading to substantial yields of the nitrenium ion in the absence of added acids. A pK! of 16 was estimated for the deprotonation of the biphenyl-4- ylnitrenium ion 30 to yield the singlet nitrene. The reactions of these relatively long-lived biphenyl-4-yl- and fluoren-2-yl-nitrenes with heterocyclic and carbon nucleophiles have been reviewed.38 Studies of the anilinylium ion 3139 have shown the reaction products to be spin state dependent.Reaction via the singlet nitrenium ion gives rise to the products of nucleophilic attack at the 4-position 32 or alkyl migration to yield the iminium ion 33 while reaction by way of the triplet leads to the amine through hydrogen abstraction. A range of primary secondary and tertiary phenylynamines have been generated flash photolytically and their reactions studied in aqueous solution.40 Under acidic conditions they undergo rate limiting protonation on Cb to yield keteniminium ions 49 Reaction mechanisms Part (ii) Polar reactions Scheme 5 (Scheme 5) followed by deprotonation on nitrogen in the case of primary and secondary ynamines to give ketenimines.The ketenimines derived from secondary ynamines undergo hydration to phenylacetamides while the ketenimine of the primary ynamine tautomerises to yield phenylacetonitrile. The keteniminum ions derived from tertiary ynamines have no nitrogen bound protons and therefore react with water to yield amide enols which then ketonise to yield the amide. The preparation and reactions of ketenes and bisketenes stabilised by silyl substituents has been reviewed.41 The techniques used in these preparations have also been applied to the generation and characterisation of the first stable and persistent 1,3- bisketene 34 and the first trisketene 35.42 Reigtz has reviewed the synthesis and reactions of nucleophilic carbenes,43 following the recent resurgence of interest in this area.An acyclic diaminocarbene 36 has been generated and studied by X-ray crystallography,44 which showed there to be considerable double bond character in the C–N bonds. 36 35 34 . . Me2Si C O C O N N Me2Si C O C O C C O The reactions of cyclopentadienylidene 37 fluorenylidene 38 and tetrachlorocyclopentadienylidene 39 generated by LFP with a range of alcohols and nucleophiles have been studied.45 Cyclopentadienylidene and fluorenylidene were found to react with alcohols to yield adducts by either rapid protonation or concerted insertion into the O–H bond whereas tetrachlorocyclopentadienylidene was shown to prefer a reaction pathway involving ylide formation. 38 37 X=H 39 X=Cl . . . . X X X X 50 IanW. Ashworth 8 Aromatic substitution Flash photolytic techniques have been applied to the study of electrophilic aromatic substitution reactions by McClelland and co-workers.46,47 The fluoren-9-yl cation was generated in the presence of a wide range of aromatic nucleophiles in HFIP.47 In the case of anisole the ortho and para substitution products were obtained and an intermediate observed which was assigned as the cyclohexadienyl cation 40.46 The formation of this cation was shown to be reversible by the kinetically determined rate constants for the loss of H` and fluorenyl cation.In the case of more electron-rich aromatics such as m-xylene and pentamethylbenzene the observed rate constants suggest a switch to an encounter-controlled process. The photoprotonation of 2- (diphenylmethyl)-1,3-dimethoxybenzene 41 in HFIP generates the cyclohexadienyl cation 42,47 which has been shown to undergo a retro-Friedel–Crafts alkylation reaction to form 1,3-dimethoxybenzene and the diphenylmethyl cation.This cation is then trapped by solvent or reacts with 1,3-dimethoxybenzene to either regenerate the starting material or form isomeric 43. Higher than expected levels of 43 at the beginning of the experiment were attributed to the intramolecular migration of the diphenylmethyl carbonation without separation of the carbocation–1,3- dimethoxybenzene complex. 44 42 41 X=CHPh2 Y=H 43 X=H Y=CHPh2 40 + + OMe Fl H X MeO OMe Y OMe OMe CHPh2 H OTf O X Solvolytic generation of acylium ions from aroyl trifluoromethanesulfonates (aroyl triflates) 44 in 1,2-dichloroethane enabled E§enberger et al.48 to study their behaviour as electrophiles in the Friedel–Crafts acylation.The reactions of a range of 4-substituted aroyl triflates 44 with anisole were studied and a break was found in the Hammett plot of the rate constants for acylation against r`. This was taken as evidence of a change in mechanism from rate limiting ionisation of the aroyl triflate with electron withdrawing substituents to rate limiting electrophilic addition with electron donating substituents. Vicarious nucleophilic aromatic substitution and other means of achieving replacement of hydrogen by a nucleophile have been reviewed by Ma�kosza.49 Such a methodology has been used to achieve selective functionalisation at the 4-position of the 2-quinolone 45 with 1,3-dicarbonyl compounds.50 The intermediate adduct 46 has been isolated and characterised and proceeds to the substitution product by the elimination of HNO 2 .An O-bonded a-adduct 47 between the enolate of acetophenone and 1,3,5-trinitrobenzene has been characterised byNMRspectroscopy at[40 °C.51 Upon warming this adduct isomerises to give the more thermodynamically stable C-adduct 48. Leaving group 18F/19F kinetic isotope e§ects have been investigated by Matsson and co-workers for the reaction of 2,4-dinitrofluorobenzene with piperidine.52 In THF 51 Reaction mechanisms Part (ii) Polar reactions 46 45 NH NO2 O O2N NO2 NH O OEt O EtO O2N NO2 O NO2 a significant isotope e§ect was observed suggesting leaving group departure to be rate limiting. A change to rate limiting addition of the nucleophile was observed when the same reaction was carried out in acetonitrile demonstrating that the nature of the rate limiting step may be a§ected by solvent in nucleophilic aromatic substitution reactions.An analysis of substituent e§ects on the rate constants for the aminolyses of 4-aryloxy-2,6-dimethoxy-1,3,5-triazines 49 demonstrated a clear dependence of reactivity upon o1'.53 Determination of b/6# for the reaction of 49 X\4-NO 2 or 3,4-NO 2 with a range of substituted pyridines also demonstrates the rate of reaction to be dependent upon the incoming nucleophile in support of the concerted substitution mechanism proposed previously. Further analysis of the experimental data for the pyridinolysis reactions in terms of Leßer exponents led to the conclusion that there is an imbalance between bond formation and bond breaking in the transition state resulting in the build up of negative charge on the triazine.References 1 R.A. 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