Research: Science and Education
Inadequacies of the S N1 Mechanism Johannes Dale Department of Chemistry, Kjemisk Institutt, Universitetet i Oslo, 0315 Oslo, Norway
The important fundamental contributions of C. K. Ingold (1) to the understanding of reaction mechanisms in organic chemistry are well recognized and have found a prominent place in modern textbooks. In contrast, his pioneering work with G. W. King (2) on the structure of electronically excited states of polyatomic molecules such as acetylene is surprisingly little known. In his theory with E. D. Hughes (3) on nucleophilic aliphatic substitution there is, however, a difficulty due to the unfortunate naming of two related groups of reactions based on an assumed difference in molecularity, SN1 and SN2. Of these only the SN2 reaction had been shown by kinetics to have a bimolecular ratedetermining step, whereas the assumed unimolecularity of the SN1 reaction cannot be proven by kinetics, the nucleophile being the solvent. The distinction was in reality based on the observed inversion of configuration when a strong nucleophile was used and became irreversibly incorporated in the product (SN2), as contrasted with the racemization observed when the solvent was the nucleophile (SN1); hence the term “solvolysis”. It was the attractive possibility to explain very simply this racemization that led to the postulation of the slow formation of a planar carbocation intermediate, followed by fast addition of solvent from either of the two sides. Critical Evaluation In the following discussion only alkyl-substituted carbocations are considered, thus excluding systems where electronically conjugated carbocations, neighboring-group participation, or nonclassical carbocations are involved. Not surprisingly, the speculative character of the SN1 mechanism has led to much uncertainty and further speculation to explain subsequent experimental data. For the physical-organic chemist the most disturbing problem has been that racemization is in most cases incomplete, the enantiomer in excess corresponding to inversion. The synthetic organic chemists had a different problem. Their experience had developed the feeling that the stereochemical outcome of simple nucleophilic substitution reactions was always that of inversion, irrespective of whether the solvent was hydroxylic and became incorporated (solvolysis), or served only as a solvent for an added strong nucleophile. This was important for the planning of many-step syntheses, and R. B. Woodward used the term “trans-ness”; other chemists prefer “anti-character”. When the substrate is heavily substituted so that the nucleophile cannot penetrate trans to the leaving group (nucleofuge), a sterically well-positioned bonding or nonbonding electron pair takes over, and the external nucleophile follows behind to pick up a correctly placed proton, the result being a stereospecific elimination. 1,2-Shifts of alkyl groups also belong to this category. Such simple examples are too well known to need presentation here, but the “domino” solvolysis of friedelanol (Scheme I) (4) is probably the world record in number of successive 1,2-hydride and methyl shifts, involving seven inversions of configuration under
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solvolytic conditions! Who can still believe in free carbocation intermediates in nucleophilic solvents?
Scheme I
An even stronger argument against the intermediacy of free carbocations is provided by stereoisomeric pairs of substrates such as tosylates, halides, or protonated epoxides. Such pairs should give identical free carbocations, hence identical solvolytic products, but they give instead dramatically different products, as exemplified by methanolysis of tosylates of the two isomeric cholesterols (Scheme II) (5) and by transannular hydride shift in the formolysis of cis- and transcyclooctane epoxides (Scheme III) (6 ).
Scheme II
Scheme III
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Research: Science & Education
Perhaps the most extreme examples are provided by the diazotation of stereoisomeric 1,2-amino alcohols. The nucleofuge being a neutral nitrogen molecule, a guaranteed quick and irreversible formation of identical carbocations, if it occurred, would be expected from each isomeric pair and, if it occurred, would give identical end products. One example is a monocyclic compound (Scheme IV) (7), each isomer existing in two conformations; the other example is multicyclic ( D-homosteroid series) (Scheme V) (8), each isomer being locked conformationally. All products are predictable assuming that an electron pair originally occupying an anti position is the one that has actually followed into the positive charge developed by the leaving nitrogen molecule! 1
Similarly, our own work on the BF 3-catalyzed cyclo-oligomerization of ethylene oxide (Scheme VII) (10) showed that neither the dimer (1,4-dioxane) nor the trimer (9-crown-3) is formed initially, but exclusively the tetramer (12-crown-4), arising from the shortest precursor chain that by folding can accommodate a linear transition state:
Scheme VII Scheme IV
The most complete and elegant proof for the inversion of configuration was provided by Hughes (11): the reaction of optically active 2-iodo-octane with radioactive iodide anion in acetone was followed by observing both the decrease of optical activity and the incorporation of radioactive iodine in the organic molecule, both giving the same rate constant.2 Thus, every act of incorporation occurs with inversion of configuration. Discussion
Scheme V
In contrast, the SN 2 mechanism stands on solid rock and was in fact already known as the “Walden inversion”. The transition state has the familiar geometry of a trigonal bipyramid with the attacking group (nucleophile) in one apical position and the leaving group (nucleofuge) in the other. Both form long half-bonds to the central carbon atom, which is coplanar with its three fully bonded substituents. This is in full agreement not only with the kinetics of a bimolecular reaction, but also with Eschenmoser’s more recent demonstration of the necessity of a strictly linear arrangement of the bonds being formed and broken (Scheme VI) (9),
Scheme VI
thus preventing the intramolecular reaction of a α -tosyl-otoluene-sulfonate in favor of the intermolecular reaction.
When I started teaching organic chemistry in 1965, many years after basic courses of “descriptive” organic chemistry, it was well established that alkyl cations are extremely reactive and can only exist in the vacuum of a mass spectrometer or in non nucleophilic solvents like the super-acids (12). Nevertheless, new textbooks discussed solvolytic displacement of halogen of alkyl halides in water or alcohol as a two-step process with the slow formation of a planar free carbocation with a lifetime long enough to be attacked equally from either side by these very nucleophilic solvents. I advised the students not to believe in the reality of free carbocation intermediates and drew their attention to other possible explanations, such as the chemical reversibility of solvolytic reactions and the different timing of the attacking nucleophile and the leaving nucleofuge. Many years later, these students remember my advice, but confess that they never believed me, since my view was not in agreement with the printed word of the textbooks. Practically all textbooks still propagate without reservation the idea of free alkyl carbocation intermediates in solvolysis. I was therefore somewhat pleased to find that in the more recent and advanced textbook by J. March (13), he “summarized” a detailed presentation of the conflicting views in this way: “The difference between the SN1 and SN2 mechanisms is in the timing of the steps. In the SN1 mechanism, first X leaves, then Y attacks. In the SN2 case,
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the two things happen simultaneously.” Still, this leaves unexplained why there is racemization and why it is not complete. One argument for the SN1 mechanism in solvolysis has been that a reactivity sequence Me3CX > Me2CHX > MeCH2X > CH3X is observed that runs parallel with the electronic stabilization of cations, while under SN2 conditions the reactivity sequence is opposite and ascribed to the reduced steric hindrance to nucleophilic attack when the substituents are hydrogen: CH3X > MeCH2X > Me2CHX > Me3CX With time the experimental data became more complex and bewildering, and Winstein (14) introduced a modification of Ingold’s mechanism based on tight ion pairs, solvated ion pairs, and solvent-separated ion pairs, so as to make the theory equally complex and bewildering. Then the simultaneous operation of the SN1 and SN2 mechanisms and the mixed or intermediate mechanisms were considered, as were borderline cases. This stimulated writers of scientific papers, troubled organic chemists, and frustrated teachers of physical-organic chemistry, to say nothing of their students. It is interesting that A. Streitwieser in his book Solvolytic Displacement Reactions (15) even has a chapter heading “Inadequacies of the SN1-Mechanism”, which I have borrowed as title for this paper because of its flavor of understatement. My basic criticism of the concept of solvated intermediate cations is that one is asking nucleophilic solvent molecules (like water or alcohols) to play two incompatible roles. On the one hand, solvent molecules are expected to approach the charge of reactive carbocations and stop at a distance presumably corresponding to that of solvated inorganic cations where covalent bond formation is impossible. On the other hand, the same solvent molecules are also asked to behave as a nucleophile and proceed the tiny remaining distance and form a stable chemical bond. What could stop them in the first place? My answer is that the problem is artificial and disappears if the idea of a two-step reaction via a carbocation intermediate is abandoned. A New Approach We are still left with two reaction types, both probably bimolecular one-step reactions with inversion of configuration. Chemical experience suggests that the primary difference is that reactions of SN2 type are irreversible and require an aggressive (often basic) nucleophile, while those of “SN1” type are more or less reversible and require the nucleofuge to be active. Examples are: R3CCl + NaOH → R3COH + NaCl irreversible, “SN2” (1) R3CCl + H2O
R3COH + HCl
reversible, “SN1”
(2)
In the former case (eq 1) nothing more can happen, and optically active alkyl chlorides give optically active alcohols with inversion of configuration. In the latter case (eq 2) we recognize that the forward solvolysis reaction produces the reagents for the backward reaction, which is nothing else than the familiar preparation of alkyl chlorides from alcohols, using
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concentrated HCl. Already, this equilibrium is the obvious explanation for the observed slowing down of the solvolysis referred to as the “common ion effect”, a term that there was no need to coin. However, this reversibility alone does not explain the observed racemization, since inversion in the forward reaction is compensated by inversion in the backward reaction (“windshield wiper”). The important point is that two species present in eq 2 can play dual roles: the chloride anion can function both as a nucleofuge and as a nucleophile, and the neutral water molecule can be a nucleophile as such, and, after protonation of the alcohol function can also be expelled as a nucleofuge. It thus becomes necessary to prove experimentally that the following two degenerate reactions are possible: R3CCl + HCl* R3COH 2䊝
+ H2O*
R3CCl* + HCl
(3)
R3CO*H 2䊝
(4)
+ H2O
Each step should occur with inversion, and if the three R groups are different, and if HCl in eq 3 or H2O in eq 4 is isotopically labeled (*), the rate of isotope incorporation and the rate of racemization should be the same. The proton required to activate the alcohol in eq 2 is furnished by the HCl produced from the R3CCl present, but reaction 4 requires a strong acid with a nonnucleophilic anion like HClO 4 as catalyst. This is of course the philosophy behind the famous experiment with optically active 2-iodo-octane and labeled iodide to prove inversion under SN2 conditions (11). Fortunately, such experiments under solvolytic conditions have been published by former collaborators of Hughes and Ingold, but seem to have been neglected. Bunton reported in 1955 that optically active 2-butanol, dissolved in aqueous perchloric acid containing 18O-enriched water, was racemized and incorporated the 18O isotope at the same rates, permitting the conclusion that every act of substitution occurs with complete inversion (16 ). Although having first formulated the reaction as bimolecular, some involved kinetic arguments were given to avoid such conclusion. In 1959 Bunton reported that t-butyl chloride, dissolved in aqueous methanol containing radioactive chloride ion, incorporates this 36Cl isotope, but inversion at carbon could of course not be demonstrated in this achiral molecule (17). This time, without arguments, it was vaguely concluded that the exchange is “apparently not an SN2 reaction”. About the same time, Dostrovsky and Klein also studied the acid-catalyzed exchange of oxygen between alcohols and water by measuring the rate of incorporation of 18O-enriched water (18). The purpose was “to determine to what extent the assumption of a carbonium-ion intermediate is justified”. It is then quite surprising that the results for the t-butyl alcohol–H2SO4 system were discussed assuming that the dissociation of the oxonium compound is rate-determining. Equally surprising is the conclusion that, although this evidence did not exclude the possibility of bimolecular attack by a water molecule on the oxonium ion, it was considered to be an unlikely mechanism for a tertiary alcohol. Such was the prestige of Ingold and the printed word! A similar study of 18O-oxygen exchange with primary alcohols (1-butanol, neopentylalcohol) led now to a firm conclusion that the mechanism is that of a bimolecular attack by a water molecule on the alcohol (19).
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Research: Science & Education
A Generalized SN Transition State
Acknowledgments
Based on these experimental findings, and not necessarily on the conclusions drawn by the authors, it can be considered as proven that reactions 2–4 do occur and are reversible. For those that have been double-tested kinetically, every act of substitution is shown to take place with inversion of configuration. Thus, there exists a mechanism for racemization under solvolytic conditions which makes unnecessary the postulation of free and solvated aliphatic carbocations as intermediates in nucleophilic media. I propose that the transition state is essentially the same in all nucleophilic aliphatic substitution reactions. It has the familiar geometry of a trigonal bipyramid with nucleophile, carbon, and nucleofuge on a straight line joining the apical positions, and with the three substituents in a plane perpendicular to it. The entering and leaving groups form weaker approximately half-bonds. In irreversible reactions the Ingold description (SN2) remains unchanged: the aggressive nucleophile will “push” the reaction so as to flatten the carbon system, and this flattening will weaken the bond to the nucleofuge on the other side until it becomes squeezed out. This explains the sensitivity to steric hindrance and the resulting reactivity order:
I thank many colleagues, in particular Einar Uggerud, for their interest and stimulating discussions.
CH3X > MeCH2X > Me2CHX > Me3CX In solvolysis the Ingold description (SN1) is rejected: the nucleofuge will “pull” the reaction, since it will generally become anionic and attracted by solvation forces and hydrogen bonding in hydroxylic solvents. This bond loosening produces a further flattening of the central carbon system, which has already started if the substitution is high. This explains the observed reversed reactivity order: Me3CX > Me2CHX > MeCH2X > CH3X Steric strain in tertiary halides may even be so dominating that the argument of electronic stabilization of carbocation intermediates by alkyl groups may lose importance. Summarizing, one can describe the difference between the two groups of SN-reactions on the basis of reagents or solvents or degree of racemization, but one may also define it on the basis of timing of bond-breaking and bond-forming and reversibility, each individual step being bimolecular with similar trigonal–bipyramidal transition states requiring inversion of configuration.
Notes 1. This generates a provocative question: Could it be that the higher stability of aromatic diazonium salts is simply due to the blocked access anti to the leaving molecule? 2. Actually, the measured rate of racemization was twice that of isotope incorporation, since each inversion produces two molecules of racemate.
Literature Cited 1. For a review see: Ingold, C. K. Structure and Mechanism in Organic Chemistry; Cornell University Press: Ithaca, NY, 1953. 2. Ingold, C. K.; King, G. W. J. Chem. Soc. 1953, 2702, 2704, 2708, 2725, 2745. 3. Hughes, E. D.; Ingold, C. K. J. Chem. Soc. 1935, 244. 4. Corey, E. J.; Ursprung, J. J. J. Am. Chem. Soc. 1956, 78, 5041. 5. Tarle, M.; Borcic, S.; Sunco, D.E. J. Org. Chem. 1975, 40, 2954. 6. Cope, A. C.; Girsar, M. J.; Peterson, P. E. J. Am. Chem. Soc. 1959, 81, 1640. 7. McCosland, G. E. J. Am. Chem. Soc. 1951, 73, 2293. 8. Cremlyn, R. J. W.; Garmaise, D. L.; Shoppee, C. W. J. Chem. Soc. 1953, 1847. 9. Tenud, L.; Farooq, S.; Seibl, J.; Eschenmoser, A. Helv. Chim. Acta 1970, 53, 2059. 10. Dale, J.; Daasvatn, K. Acta Chem. Scand. 1971, 25, 725. 11. Hughes, E. D.; Juliesburger, F.; Masterman, S.; Topley, B.; Weiss, J. J. Chem. Soc. 1935, 1525. 12. For a review see Olah, G. A. Angew. Chem. Int. Ed. Engl. 1973, 12, 173. 13. March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; p 255–268. 14. Winstein, S.; Clippinger, E.; Feinberg, A. H.; Heck, R.; Robinson, G. C. J. Am. Chem. Soc. 1956, 78, 328. 15. Streitwieser, A. Solvolytic Displacement Reactions; McGraw-Hill: New York, 1962. 16. Bunton, C. A.; Konasiewicz, A.; Llewellyn, D. R. J. Chem. Soc. 1955, 604. 17. Bunton, C. A.; Nayak, B. J. Chem. Soc. 1959, 3854. 18. Dostrovsky, I.; Klein, F. S. J. Chem. Soc. 1955, 791. 19. Dostrovsky, I.; Klein, F. S. J. Chem. Soc. 1955, 4401.
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