J. CHEM. SOC. PERKIN TRANS. 11 1985 Halogen Mobility in SN2Reactions of Carbonyl Compounds. Comparisons with Aromatic Halogen Mobility t Joseph Miller' and Oi-Ling Ying Universadade de Sa'o Pauto, Facutdade de Filosofia, Ciencias t?? Letras de Ribeirgo Preto, Departamento de Quimica, 14.100Ribeira'o Preto SP, Brasil ~ ~~ Kinetic studies, using conductimetric techniques, have been carried out for isopropanolysis (solvolysis) reactions of some alkanoyl, benzoyl, and perfluoroalkanoyl halides, viz. butanoyl and benzoyl fluorides, chlorides, and bromides and perfluoropentanoyl fluoride and chloride. The halogen mobility orders, F 4 CI < Br, have been compared with mobility patterns recognised for SNreactions at saturated and aromatic carbon, and have been discussed in mechanistic terms.The substrate class reactivity order is perfluoroalkanoyl 9 benzoyl, alkanoyl. The actual ratios depend on which halogen is displaced, the ratios being larger in displacement of fluorine. Halogen mobility can be highly indicative of details of mechanism. Our long-term studies of this in SNAr reactions are relevant to the present discussion and can be summarised as follows. (i) The addition4imination SN2 mechanism via a (3-complex is the principal mechanism, with reaction profiles in which there is a deep potential energy well. Thus, even in displacement of fluorine the formation of the first or second transition state may be rate limiting. (ii) There is an elec tronega tivity factor favouring displacement of fluorine, compared with the heavy halogens, which the depth of the potential energy well allows to be kinetically significant in many reactions.As a result, the halogen mobility orders F 9Cl, Br, I, F 4 Cl, Br, I, and a few intermediate cases are well known. The high fluorine mobility pattern, observed for example in alcoholysis (solvolysis), is illustrated by curves A and B of Figure 1, and is based on ref. 5. Our key suggestion for interpreting the acyl halide alcoholyses (solvolyses), studied by us, is that these reactions also proceed by an addition-elimination SN2-type mechanism, but with a shallower potential energy well. This suggestion and its consequences are elaborated and discussed below, but it is convenient to present at this point a pair of reaction profiles for acyl fluoride and chloride alcoholysis (solvolysis) (curves C and D of Figure 1)which correspond to our suggestion, while maintaining the general character of addition-elimination SN2 displacement of halogens.In Figure 1 the differences in heights of transition state 1 of curves A and B and of curves C and D correspond to the electronegativity factor mentioned above. Differences in heights of transition state 2 of curves A and B and of curves C and D correspond to the differences in intrinsic mobility of fluorine and chlorine in corresponding situations. It is also convenient, however, to recall that S,l reactions of RCOLGN compounds (LGN= nucleofugal group) are It is accepted that such reactions, of e.g.acyl halides, occur only in propitious circumstances, including the structure of R such that it lends additional stabilisation to the forming acylium ion [RC=O]'. It is also convenient to add that various authors (e.g. see ref. 10 and papers cited therein) assert that a synchronous &2 mechanism, analogous to that at saturated carbon, may be utilised. It is surprising how little serious attention has been directed to halogen mobility (or indeed that of other nucleofugal groups) in SNreactions of carbonyl cornp~unds.~-' t This work was reported at the Sixth IUPAC Conference on Physical Organic Chemistry, Louvain-la-Neuve, 1982. In virtually all cases which include the mobility of fluorine, the reactions studied are of hydrolysis, and show fluorine as much less mobile than the heavy halogens, where the mobility order is I > Br > C1.There is however one report l2 of the reactions of benzoyl chloride and fluoride with OH- in 50% ethanol-water in which the F:Cl mobility ratio is 1.4:1 at 0"C. Though the experimental work now reported was carried out a considerable time ago l3 its purpose still stands, uiz., to contribute to knowledge of leaving group, especially halogen, mobility in S, reactions at heteropolar unsaturated carbon and to discuss the relation to the mechanism probably involved. In addition, the work was conceived for the purpose of extending our knowledge of the reactivity of electrophilic carbon centres. We selected as substrates butanoyl fluoride, chloride, and bromide, benzoyl fluoride, chloride, and bromide, and perfluoropentanoyl fluoride and chloride.The reaction selected for study was isopropanolysis (solvolysis) in anhydrous conditions, and we followed rates by measuring conductivity changes. The choice of isopropanolysis was based on the following considerations. (i) We could follow the reactions using conventional equipment; (ii) the conductivity values were adequate; (iii) we judged that there would be no possibility of an S, 1 reaction. It is worth recalling that in some recent work 778 we showed that benzoyl chloride follows an SN2 mechanism even in methanolysis (solvolysis), while alkanoyl and perfluoro-alkanoyl chlorides would be less susceptible to reaction by an SN1 mechanism.Experimental Preparation of Materials and Solvents.-Butanoyl chloride was the commercial product redistilled twice to b.p. lo@-101 "C (lit.,14 101-101.5 "C). Butanoyl fluoride was prepared by reaction of anhydrous butanoic acid with oven-dried KHF, under reflux (3 h). After two distillations it had b.p. 66-67 "C (lit.,15 67"C). Butanoyl bromide was prepared by reacting anhydrous butanoic acid with PBr, at ambient temperature. After two distillations it had b.p. 127"C (lit.," 128 "C). Benzoyl chloride was the commercial product redistilled several times to b.p. 196"C (lit.," 196.2-196.5 "C). Benzoyl fluoride was prepared from the purified chloride by reaction with oven-dried KHF, under reflux (3 h). After three fractional distillations it had b.p.154"C (lit.," 155-156 "C). Benzoyl bromide was prepared by reacting dried benzoic acid with PBr, at ambient temperature. After distillation several times at reduced pressure, 324 J. CHEM. SOC. PERKIN TRANS. 11 1985 T. St. 1 T St. 2 1: St. 2IAL I. st. A B F.St L t F. StF.4 Reaction co-ordinate Figure 1. Types of reaction profile suggested for alcoholysis (solvolysis): A, displacement of fluorine from an activated aryl fluoride; B, displacement of chlorine from the corresponding chloride; C, displacement of fluorine from an acyl fluoride; D, displacement of chlorine from the corresponding chloride. I.St. = Initial state; I.C. = intermediate complex; F.St. = Final state; T.St.1 and T.St.2 = transition states 1 and 2 t/min Figure 2First-order plot for reaction of perfluoropentanoyl chloride in absolute propan-2-01 at -52 "C we recorded b.p. 218 "C (1it.,l8 218-219 "C). Perfluoro-pentanoyl chloride was the commercial product redistilled twice to b.p. 67-48 "C (lit.,19 67.5-68 "C). Perfluoropentanoyl fluoride was obtained from the purified chloride by reaction with oven-dried KHF, under reflux (3 h). After two fractional distillations it had b.p. 45-47 "C(lit.,20 b.p. not recorded). For all these preparations oven-dried glassware was used and -5.0 d -5.1 -52 -5.31 Figure 3. Arrhenius plot for reaction of benzoyl fluoride in absolute propan-2-01 precautions taken to avoid entrance of moisture. Propan-2-01 was purified according to Vogel." Conductivity water was prepared from distilled water by reflux with KMnO, and KOH and re-distillation. Entrance of CO, to the receiver was avoided.Thermostats.--Below -20 "C,dry-ice-ethanol mixtures in a Dewar flask were used. This gave acceptable temperature control (f0.3 "C) for the reaction times used. For other J. CHEM. SOC. PERKIN TRANS. 11 1985 Table 1. Experimental rate coefficients (k2/mol-' s-') for the isopropanolysis (solvolysis) of some carbonyl halides (logarithmic exponents in parentheses) Groups linked to CO & Rate coefficient T/"C Group linked to CO & Rate coefficient T/"C C3H7 C3H7 C3H7 F C1 Br 1.31 (-6) 1.84 (-6) 2.44 (-6) 3.40 (-6) 5.17 (-6) 5.22 (-6) 7.55 (-6) 1.10 (-5) 2.01 (-4) 1.48 (-5) 1.38 (-4) 1 10.0 115.0 120.0 125.0 25.0 25.1 30.0 34.8 39.4 -20.0 -15.0 C6H5 C6H5 C4F9 c1 Br F 7.27 (-6) 8.39 (-6) 9.81 (-6) 1.50 (-5) 5.12 (-6) 1.04 (-5) 2.09 (-5) 4.02 (-5) 3.18 (-5) 7.34 (-5) 1.61 (-4) 25.0 27.0 29.6 35.0 -23.0 -16.0 -6.0 +0.5 -30.0 -20.0 -10.0 2.93 (-4) -10.0 3.33 (-4) +0.1 5.83 (-4) 4.11 (-6) 8.60 (-6) 1.20 (-5) 2.68 (-5) 0.0 80.0 90.8 96.3 109.1 C4F9 C1 1.26 (-4) 1.76 (-4) 2.82 (-4) 4.11 (-4) 6.38 (-4) -61.0 -57.0 -52.0 -47.0 -42.0 Table 2.Rate coefficients and Arrhenius parameters for the isopropanolysis (solvolysis) of some carbonyl halides at 25 "C (logarithmic exponents in parentheses) Substrate reactivity Groups linked Rate coefficient Halogen Activation Frequency ratios displacing to c=o k2 mobility ratio energy (LIE+/ factor log,, (I mol-I s-I) c1 = 1 kJ mol-') (A/mol-' s-I ) 8.4, (-10) 1.6, (-4) 80.5.29 5.17 (-6) 1 (0) 57., 4.8, 2.7, (-3) 5.24 (2) 41., 4.7, 4.28 (-8) 5.9, (-4) 72., 5.3, 7.1, (-6) 1 (0) 56., 4.7, 2.72 (-4) 3.8 (1) 49.8 5.16 1.6, (-3) 4.6 (-2) 43., 4.7, 3.5, (-2) 1 (0) 34.5 4.9, temperatures standard water- or oil-bath thermostats were used Analysing the kinetic data in detail (see Table 2), a number of with temperature control to better than kO.1 "C. very interesting features emerge. In the three series studied, the order of mobility F < C1 is Conductivity Measurements and Rate Constants.-Conduc- clearly evident. In two of the series, in which the mobility of tivity measurements were made with an LKB 3216B bromine was also determined, the extended order F < C1 < Br conductivity bridge, and related to concentrations of products is evident.The detailed analysis shows however that the relative by prior calibration. Above 40°C a sealed conductivity tube fluorine:chlorine mobilities increase sequentially in the series was used, allowing 15 min for it to attain thermostat RCOHal, PhCOHal, RFCOHal for which F:C1 mobility ratios temperature. For lower temperatures a cell with main and are 1.64 x lop4,5.98 x 10 3, and 4.6 x lop2 respectively. subsidiary containers was used which permitted the thermostat In the change from RCOHal to PhCOHal the Br:Cl temperature to be attained before mixing. mobility ratio decreases substantially, from 524 to 38.The second-order rate coefficients were obtained from the Because of these changes the substrate reactivity ratios solvolysis (first order) rate coefficients, dividing them by the depend on which halogen is displaced. In displacement of molar concentration of solvent. The first-order rate coefficients fluorine, the perfluoroalkanoyl compound is over lo6 times were obtained graphically. Experimental rate coefficients are more reactive than the alkanoyl compound whereas it is only ca. given as Table 1. Examples of determinations are given as '7 x lo3times more reactive in displacement of chlorine. In the Figures 2 and 3, uiz., the first-order rate plot for isopropanolysis intermediate position, benzoyl fluoride is ca. 50 times more of perfluoropentanoyl chloride at -52 "C and the Arrhenius reactive than butanoyl fluoride whereas the benzoyl and plot for benzoyl fluoride.Estimated errors in k, are ca. 1%. butanoyl chlorides have about equal reactivity. In displacement of bromine the benzoyl compound is ca. 10times less reactive. The substrate reactivity ratios, RCOHal -PhCOHal 4 RF-COHal, are what one would expect in relation to electron Discussion deficiency at carbonyl carbon, and to conjugative interactions. The halogen mobilities encountered in our studies are We did not need, nor seek, kinetic data of high precision. It is consistent with the limited number of studies reported in the gratifying therefore that the Arrhenius parameters are so well literature.9-1 behaved. The values of the frequency factor, given as log,, A, are all virtually identical, falling in the range 5.03 f0.32.They are what one might expect for a reaction between neutral substrates forming ions in a protic ~olvent.~ As a consequence reactivity differences are enthalpy-dependent. In displacement of fluorine AE' values are 80.1, 72.4, and 42.1 kJ mol-' (alkanoyl, benzoyl, perfluoroalkanoyl). In displacement ofchlorine the lower AE' values are 57.5,56.5, and 34.5 kJ mol-' respectively. The differing F:Cl mobility ratios correspond to AAE' values of 38.6, 22.6, and 8.6 kJ mol-'. AE' Values are lowest with the bromo compounds, varying from 41.5 (alkanoyl) to 49.8 kJ mol-' (benzoyl). In discussing our results, we feel it necessary to make a number of general comments, making comparisons especially with halogen mobilities in SNAr reactions, which we have studied in considerable depth.' We put forward and comment on the following mechanistic possibilities, and their ability or otherwise to explain the experimental results.The first of these is that the reactions proceed by a synchronous SN2 mechanism, which excludes any change in the bond order of the carbon--oxygen double bond and thus corresponds to the SN2 mechanism at saturated carbon. The second proposition is that the reactions proceed by a pure addi tion-elimination SN2 mechanism, passing through a fully bonded tetrahedral intermediate which corresponds to a minimum in the reaction profile [analogous to the normal (activated) SNAr mechanism] but differing from it in having a relatively shallow potential well.The third proposition is that the reactions proceed by a 'mixed' addition-elimination SN2 mechanism, corresponding to that suggested by Ingold 22 for carboxy and amide reactions. This also passes through a tetrahedral intermediate, which corresponds to a minimum in the reaction profile. The difference from the pure mechanism is the suggestion that in the intermediate, and in the first, as well as second, transition states there is some degree of rupture of the carbonyl-halogen bond. In theye circumstances it seems reasonable to assume that the isopropoxy-carbon bond is not fully formed, at least in the first transition state and perhaps in the tetrahedral intermediate also.It seems to us extremely improbable that the carbonyl halide solvolyses follow a synchronous SNmechanism, when one bears in mind that there is a polarisable n-bond at the electrophilic reaction centre linking carbon to the very electronegative oxygen atom. Further, this bond, though quite strong, is considerably weaker than the C-F bond and about equal in strength to the C-Cl bond. The mechanism seems to us incompatible with the F :Cl mobilities encountered in alkaline hydrolysis of benzoyl chloride and fluoride,12 bearing in mind that there is no record in the literature of synchronous SN2 reactions in which fluorine is not substantially less mobile than the heavy halogens. The synchronous mechanism is not needed to explain the lower mobility of fluorine than of the heavy halogens (see below) and we regard it as incompatible with the much higher reactivity of perfluoroalkanoyl than of alkanoyl halides.It is also inconsistent with oxygen-exchange data." Furthermore, the very large differences in bond order necessary for the synchronous SN2 mechanism to explain our results, even in part, are inconsistent with the near constancy of the log A term. In relation to the addition-elimination SN2 mechanism for the SN2 carbonyl substitutions we make the following comments on our suggestion of a shallower potential well, when compared with SNAr reactions. The tetrahedral SNAr intermediates (benzenide or o-complex) are species which are highly conjugated; and this is much enhanced when suitably placed conjugative electron- withdrawing groups are present.This concept, which suggests J. CHEM. SOC. PERKIN TRANS. II 1985 (Ar 1R \C /-OCHMe2 Ha 1 ''OH as an example equal levels of conjugative stabilisation of 2,4- dinitrobenzenoid and 2,4-dinitrobenzenide systems, gains strong support from the agreement with experiment of numerous thermochemical calculations of SNAr reactions, 1*23 which incorporate it. In contrast, as the acyl halide reactions proceed, positive charge begins to develop on the isopropoxy oxygen (Me2CH- OH6+----), while negative charge begins to develop on the erstwhile carbonyl oxygen (C4 ). These are highly acidic and basic centres respectively, and we suggest that there is an early proton transfer, essentially complete by the formation of the first transition-state.For simplicity, we present the subsequent tetrahedral intermediate in the fully-bonded form (1).We surmise that this intermediate is less stable than the reactant, as is ester hydrolysis. One can speculate on loss of conjugation (ArCO case), or of polarisation-hyperconjugation (RCO case) as factors involved while it is reasonable to speculate that solvation factors favour the SNAr intermediate in comparison with the acyl halide intermediate. With a shallow potential energy well it would not be possible to have reactions in which the formation of transition state 1 is rate-limiting in displacement of fluorine. With a powerful reagent one might, as an exceptional case, have a reaction displacing fluorine in which although the formation of transition state 2 is rate-limiting the difference in energy transition state 2 -transition state 1 is less than the electronegativity effect discussed below.Thus the pure addition- elimination SN2 mechanism is adequate to explain F:Cl mobility ratios considerably less than unity, as well as the F:Cl mobility ratio of 1.4, obtained in an alkaline hydrolysis reaction. ''*2-59 This brings forward the necessity to comment on the electronegativity effect so important in SNAr reaction^'*^^-^^ and which should be involved in the details of the reaction profiles of addition4imination SN2 reactions in general. An electronegative group reduces electron density on the electrophilic carbon to which it is attached and thus facilitates nucleophilic attack.This has an observable kinetic effect only when (i) the formation of transition state 1 is rate-limiting or (ii) in those cases in which the formation of transition state 2 is rate- limiting, where the difference of energy transition state 2 -transition state 1 does not exceed the amount by which the electronegativity effect reduces transition state 1. Examples are shown in ref. 4. As regards displacement of fluorine and chlorine we have suggested that the electronegativity difference between F and C1 causes a reduction in transition state 1 in displacement of fluorine approximately equal to 13 kJ mol-' (see particularly refs.1, 2, and 23). The results of Swain and Scott l2 with F:Cl 1.4 correspond closely to this difference between transition states 1 and 2. The pure addition-elimination SNmechanism fails in not explaining the quite high Br: C1 mobility ratios observed in the carbonyl reactions (some high 1:Cl ratios have also been observed lo). We stress that in SNAr reactions which proceed by the addition-elimination S,2 (principal) mechanism, there is no known case where bromine is substantially more mobile than is chlorine and never even approaches the values shown by our work. Bromine is normally less mobile than chlorine.' On the basis of the preceding comments we suggest therefore that the reactions of the chlorides and bromides occur via the J.CHEM. SOC. PERKIN TRANS. 11 1985 ‘mixed’ addition-elimination sN2 mechanism, mentioned earlier. Since all the intermediates involve carbonyl-halogen bond rupture, it is difficult to conclude with any certainty which is the rate-limiting step formation of the first or second transition state. It does seem however that there is more carbonyl-halogen bond rupture in the alkanoyl than in the benzoyl series (see below). We consider that the fluorides react by the pure addition-elimination sN2 mechanism, with the formation of the second transition state as the rate-limiting step (see above). We believe that our comments are equally valid for other solvolytic reactions in hydroxylic solvents. The reactions with OH -,already mentioned, and reactions of strong nucleophiles in general, probably follow our version of the pure addition-elimination &2 mechanism.We do not consider that our comments are in any way weakened by the occurrence of the halogen mobility order F < C1 < Br < I in &2 reactions at saturated carbon, nor that the mobility order F < C1, Br, I is encountered in SNAr reactions with many heavy nucleophiles * and/or in poorly ionking solvents. The spectrum of halogen mobilities in SNAr reactions has been fully rationalised.’ One additional point needs to be made abundantly clear. We recognise that the relatively low dieletric constant of propan-2- 01 compared with water and methanol, or even ethanol, should reduce its ability to solvate ions in preference to interactions leading to formation of ion-pairs or multiplets or a crystal lattice.This cannot, however, be responsible for the halogen mobility order (especially F 4Cl) encountered in our work. This is amply demonstrated by our other studies on solvolytic hydrolysis and alcoholysis, including isopropanolysis, of picryl chloride and fluoride. In all these reactions fluorine is much more mobile, and F:CI mobility ratios differ little from each other.572 * Nucleophiles whose reactive centre is an atom of the second or higher row of the Periodic Table. References 1 J. Miller, ‘Aromatic Nucleophilic Substitutions,’ Elsevier, Amster- dam, 1968, chs. V and VI. 2 J. Miller, Aust. J. Chem., 1969, 22, 921. 3 F.H. Kendall, J. Miller, and R. Wong, J. Chem. SOC.B, 1971, 1521. 4 J. Miller and H. W. Yeung, J. Chem. SOC.,Perkin Trans. 2,1972,1553. 5 K. B. Lam, J. Miller, and P. J. S. Moran, J. Chem. Soc., Perkin Trans. 2, 1977, 457. 6 D. A. Brown and R. F. Hudson, J. Chem. SOC.,1953,883. 7 P. C. Ferreira, N. Z. Kiyan, Y. Miyata, and J. Miller, J. Chem. Soc., Perkin Trans. 2, 1976, 1648. 8 J. A. L. Jorge, N. Z. Kiyan, Y. Miyata, and J. Miller, J. Chem. SOC., Perkin Trans. 2, 1981, 100. 9 P. Sykes, ‘A Guidebook to Mechanism in Organic Chemistry,’ Longmans, London and New York, 5th edn., 1981, pp. 232-238. 10 A. Kivinen in ‘The Chemistry of Acyl Halides,’ ed. S. Patai, Interscience, London, New York, Sydney, Toronto, 1972, ch. 6 and references quoted therein.11 R. E. Parker, Ado. Fluorine Chem., 1963,3, 63. 12 C. G. Swain and C. B. Scott, J. Am. Chem. SOC.,1953, 75, 246. 13 0.L. Ying, M.Sc. Thesis, University of Hong Kong, 1966. 14 G. T. 0.Martins and J. R. Partington, J. Chem. SOC.,1936, 62. 15 A. I. Mashentev, Zh. Obshch. Khim, 1945, 15, 918. 16 L. Berthelot, J. Chem. Soc., 1857, 344. 17 A. T. Dann, W. Davies, A. N. Hambly, R. E. Paul, and G s. c. Semmens, J. Chem. Soc., 1933, 15. 18 W. Davies, A. N. Hambly, and G. S. C. Semmens, J.Chem.Soc 1933, 1309. 19 J. H. Simons, W. T. Black, and R. F. Clark, J. Am. Chem. SOC.,1953, 75, 5021. 20 W. A. Severson and T. J. Brice, U.S. P. 2,765,326 1956 (Chem. Abstr., 1957, 51, 5819). 21 A. I. Vogel, ‘A Textbook of Practical Organic Chemistry,’ 3rd edn., Longman, London, 1970, p. 170. 22 C. K. Ingold, ‘Structure and Mechanism in Organic Chemistry,’ Bell, London, 1969,2nd. edn., pp. 1 132,1134,1155,1165,1167, and 1 168. 23 J. Miller, J. Am. Chem. SOC.,1963, 85, 1628. 24 J. Miller, Reo. Pure Appl. Chem., 1951, 1, 171. 25 A. L. Beckwith, J. Miller, and G. D. Leahy, J.Chem.SOC.,1952,3532. 26 J. Miller and P. J. S. Moran, (a)J.Chem. Res., 1980, (S)62; (M)0501; (h) unpublished work. Received 5th October 1982; Paper 2/1713