Subject Chemistry Paper No and Title Module No and Title Module Tag 5; Organic Chemistry-II 13; Mixed S N 1 and S N 2 Reactions CHE_P5_M13
TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Nature of substrate is deciding factor for borderline mechanism 4. Competition between S N 1 and S N 2 mechanisms 4.1 Concentration of nucleophile 4.2 Reactivity of nucleophile 4.3 Solvent effect 5. Summary
1. Learning Outcomes After studying this module, you shall be able to Know about mixed S N 1 and S N 2 mechanism Acquire factors influencing S N 1 and S N 2 mechanism Identify borderline cases Evaluate parameter leading to a mechanistic borderline Analyse factors governing reaction mechanisms 2. Introduction In a Nucleophilic substitution reaction a nucleophile (electron rich species) bonds with a positive/partially positively charged centre in a substrate expelling the leaving group. The two factors i.e. molecularity and reaction kinetics, classifies nucleophilic substitution mechanisms as substitution nucleophilic unimolecular (S N 1) and substitution nucleophilic bimolecular (S N 2). Where the S N 1 mechanism is a two step mechanism, involving carbocation intermediate whereby the product of the reaction is a racemic mixture and the S N 2 mechanisms proceed in a single step through a transition state whereby the reaction leads to inversion of configuration. Example of S N 1 mechanism: Example of S N 2 mechanism: There is only difference in the timing of the steps between S N 1 and S N 2 mechanisms. On one hand in the S N 1 mechanism, first the leaving group leaves followed by the nucleophile attack whereas, in the S N 2 mechanism, the two things happen simultaneously. But some times under a
given set of conditions there are reactions that are known to proceed with a mechanistic borderline region i.e mixed S N 1 and S N 2. Example of mixed S N 1 and S N 2 mechanism: Classically these two proposals defined the mixed S N 1 and S N 2 mechanisms: a) Neither a pure S N 1 nor a pure S N 2 mechanism operates but some in-between mechanism is operative leading to both inversion and racemization of products. b) In the same reaction mixture, some molecules react by the S N 1, while others react by the S N 2 mechanism simultaneously. A research work was done by Sneen et. al, according to which the entire S N 1 or S N 2 mechanistic spectrum could be fitted into a simple scheme involving ion-pair intermediates accomodating features of both S N 1 and S N 2 reactions. According to the proposed mechanism, the substrate is first ionized to an intermediate ion pair which then leads to the formation of final products as follows; What can be inferred from the above equation is that for S N 1 mechanism the formation of the ion pair (k 1 ) is rate determining, while in the S N 2 mechanism its destruction (k 2 ) is rate determining. And where the rates of formation and destruction of the ion pair are of the same order of magnitude, there mixed S N 1 and S N 2 mechanisms are observed. The Experimental evidence suggests that the borderline mechanism or mixed S N 1/S N 2 mechanism were shown by benzyl chloride hydrolyses in aqueous solvents. The substitution proceeds with a clear S N 2 mechanism. However, upon p-substitution, p-methoxybenzyl chloride solvolysis takes place by the S N 1 route. As the para substituent changes from the order of electron withdrawing to electron donating functional groups (NO 2, Cl, H, CH 3, OCH 3 ),a progressive change from the bimolecular mechanism to the unimolecular pathway is observed. The intermediate situation for p-methylbenzyl chlorides was found to be border line where it was argued that S N 1 and S N 2 processes occur side by side. With the addition of azide ions (good nucleophile) to the reaction, the alcohol is still there as a product, but 4-methoxybenzyl azide comes out to be another product. The role of additional nucleophile azide ions is thus to increase
in the rate of ionization (by the salt effect) but decreases the rate of hydrolysis. Thus, both S N 1 and S N 2 mechanisms were shown to be operative simultaneously. Previously, for a borderline mechanism the most important indications were partial racemization and partial inversion of products. However, Weiner and Sneen demonstrated that this type of stereochemical behaviour is consistent with a strictly S N 2 process where double inversion takes place leading to racemization. In another view, Schleyer et. al proposed that solvent assistance to ion-pair formation is the key to the mixed mechanism behavior. Schleyer et al on the other hand criticized the ion pair concept of mixed S N 1/S N 2 mechanism suggested by Sneen et al and proposed that there is a gradation of transition states between the S N 1 and S N 2 extremes with varying degrees of nucleophilic participation by the solvents. The borderline region was considered to be one where nucleophilically solvated ion pairs were involved which basically looked like the transition states of S N 2 reactions. With the recent study of reaction kinetics it was led to an argument that nucleophilic substitutions at saturated carbons occur by the stepwise S N 1 mechanism where the lifetime of intermediate carbocations decides reaction pathway. The term borderline therefore implied to the existence of a line separating S N 1 from S N 2, whose position depended on the lifetime of the reaction intermediate. When the carbocations exist in energy wells for at least the time of a bond vibration ( 10-13 s) S N 1 mechanism follows which changes to the S N 2 mechanism if the energy well for the intermediate disappears. Reaction co-ordinates with intermediate lifetime for nucleophilic substitution
The above schematic representation conveys about reaction co-ordinates that distinguishes between mechanisms based on lifetime of intermediates. It is only unstable or the steady state intermediates which were considered to not accumulate during the reaction. Basically two borderlines were considered: (A) between mechanisms where intermediate does not play any role and mechanisms that depends more on intermediates in a stepwise manner, secondly (B) between mechanisms where the intermediate either does or does not have enough lifetime to diffuse through the solvent before reacting with a catalyst or another reactant. If in case the intermediate does not exist or is too unstable to diffuse through the solvent, a pre association mechanism is followed in the reaction in which the reactants, be it the final reactant or catalyst, C, they assemble before the first bond-making or -breaking step take place. Convincing grounds has been set for this hypothesis. Let us take an elegant example in which : benzhydryl bromides 1-X,Y were made to react with amines in DMSO giving benzhydryl amines (4), benzophenones (5), and benzhydrols (6) as products. For the reaction under several cases, first-order rate constants k 1 for the formation of the carbocations were observed which were similar in magnitude as the second-order rate constants k 2 for the concerted S N 2 reactions. As the change is observed from S N 1 to S N 2 mechanisms when the lifetimes of the carbocations in the presence of amines were calculated which came to be approximately 10-14 s, these parameters were used by the authors to calculate reaction pathway suitable enough for predicting the preferred mechanism of the nucleophilic substitutions of benzhydryl bromides. Thus the lifetime dependent switching of mechanism was confirmed. 3. Nature of substrate is deciding factor for borderline mechanism
Primary and secondary substrates generally react by the S N 2 mechanism and tertiary by the S N 1 mechanism. However, tertiary substrates seldom undergo nucleophilic substitution, as competing elimination is always a possible side reaction and with tertiary substrates it usually predominates. In an experiment relative reactivity of the different alkyl halides towards S N 1 and S N 2 reactions were determined. According to what is noticed, as one passes along the series of halides (from left to right), the first and last member readily undergoes hydrolysis on the other hand the intermediates are somewhat resistant to hydrolysis. In the investigation of kinetics of the reaction what was observed is a change in the order of reaction whereby the reactivity by the S N 2 mechanism decreases from CH 3 to primary C atoms, and at a secondary C atom the reactivity is so low that the S N 1 starts to contribute significantly, rising sharply to tertiary C atoms. Experimentally, the rate of hydrolysis with dilute aqueous ethanolic sodium hydroxide gave the following plot; The minimum in the curve is attributed to a shift in the reaction mechanism form S N 2 to S N 1. Moreover the effect of electronic and stearic factor on transition state of each substrate was considered to explain this change of mechanism in each case. For S N 2 mechanism the enhanced inductive effect of CH 3 group makes the carbon less positively charged and thus less polarized. Hence it is less readily attacked by the hydroxide ion. This inductive effect is however small as compared to the associated steric bulk as a result of which hydroxide will find it progressively more difficult to attack a tertiary carbon than a primary carbon. The more crowded the transition state is relative to the starting material, the higher is its energy and therefore slower will be the reaction. Experimentally, for the reaction (Br - + R-Cl) under strictly S N 2 conditions it was shown that the rate were as follows;
On the other hand for S N 1 mechanism as carbocation intermediate is stabilized by both inductive and hyper conjugative effect of methyl groups; therefore as the above series of halides is traversed there is increasing stabilization of transition state, hence there is an increase in the rate of S N 1 reaction. The observed hyper conjugative effect is maximum for tertiary carbocation, as there are nine H atoms available for hyper conjugation. As for the stearic effect since the carbocation is planar with sp 2 hybridization so there is less crowding in the transition state than in the initial sp 3 hybridized alkyl halide. The S N 1 mechanism is therefore preferred on inductive as well as stearic grounds in the order of H<CH 3 <(CH 3 ) 2 <(CH 3 ) 3. This explains the shift of S N 2 mechanism to S N 1 mechanism across the halide series quoted above. The effect of structure on relative reactivity is quite evident when the leaving group such as halogen is placed at the bridgehead of a bicyclic system. The experimentally observed rate of solvolysis for following substrates in 80% aqueous ethanol were as follows; For these substrates the reaction will go typically slowly due to unfavorable geometry of intermediates in S N 2 mechanism as well as ion pairing S N 1 mechanism. This is because for bicyclic substrates the backside attack is prevented owing to their stearically hindered location as
well as cage like structure which makes it impossible to acquire planar structure as is observed in both S N 1 and S N 2 mechanisms. 4. Competition between S N 2 and S N 1 mechanism 4.1 Due to stability of intermediate carbocation formed, primary alkyl halides prefer to undergo substitution by S N 2 mechanism whereas tertiary alkyl halides by S N 1 mechanism. However, secondary alkyl halides, benzylic and allylic groups may undergo substitution either by any single mode or even the experimental conditions may lead to a mixed substitution mechanism. The experimental conditions that determine which mechanism will predominate are: Concentration of nucleophile Reactivity of nucleophile Solvent 4.1.1 Concentration of nucleophile The rate law for S N 1, S N 2 and mixed S N 1/S N 2 reactions are as follows S N 1 S N 2 Mixed S N 1/S N 2 Rate = k 1 [substrate] Rate = k 2 [substrate][nucleophile] Rate = k 2 [substrate][nucleophile] + k 1 [substrate] The rate law equations make it clear that an increase in concentration of nucleophile increases rate of S N 2 reaction but having no influence on S N 1 mechanism. Therefore when both reactions compete with each other in a reaction mixture, on increasing the nucleophile concentration the fraction of reaction that takes place by S N 2 mechanism is the more preferred one. In contrast, the decrease in nucleophile concentration would decrease the fraction of reaction that takes place by S N 1 pathway. 4.1.2 Reactivity of nucleophile The nucleophile participates in rate determining step in S N 2 mechanism. Therefore, with the increase in reactivity of nucleophile, the rate of S N 2 reaction increases by increasing the value of rate constant (k 2 ), as more reactive nucleophile would displace a leaving group in a better way. On the other hand, there is no effect of nucleophile reactivity on S N 1 mechanism, therefore a poor nucleophile would undergo S N 1 mechanism and a better nucleophile will increase fraction of S N 2 mechanism when both reactions are competing.
4.1.3 Solvent If the change in concentration of nucleophile has no effect on the rate of a reaction then it is S N 1 reaction. If there is an effect then the reaction must be S N 2. A remarkable role is played by the solvent properties on the rates of these two types of reactions. If the solvent is the nucleophile in a substitution reaction, then the process is called solvolysis. For such reactions it is difficult to predict the mechanism that whether it is S N 1, S N 2 or mixed mechanism as the reaction would follow a first order kinetics due to excess of solvent present. Rate = k[r-x] This is because for S N 2 mechanism the concentration of nucleophile will remain practically constant throughout, as being solvent it will always be present in large excess. Therefore, it becomes difficult to predict nature of mechanistic pathway based on stereochemistry of products. In general, polar solvents with high dielectric constants (water - 81, ethanol - 25 and acetone - 21) increase the rate of S N 1 reactions. This is because in S N 1 there is formation of intermediate carbocation, where solvent facilitates the stability of separated ions which would lower the activation energy for this step, thus enhancing rate of reaction. Therefore, increasing the polarity of the solvent will decrease the difference in energy between them, in turn increasing the rate of the reaction, as shown in Figure 1 A and B Fig 1 (A) represents reaction coordinate diagram for a reaction in which the charge on the transition state is greater than the charge on the reactants.
Fig 1 (B) represents reaction coordinate diagram for a reaction in which the charge on the reactants is greater than the charge on the transition state. For S N 2 mechanism, polar solvents stabilize the reactants more than the transition state as the charge is more dispersed in the transition state therefore; polar solvents slightly decrease the rate of S N 2 reactions. If the charge on the reactants is greater than the charge on the rate-determining transition state, a polar solvent will stabilize the reactants more than it will stabilize the transition state which will increase the difference in energy between them. Consequently, increase in the polarity of the solvent will decrease the rate of the reaction as shown in Figure B.
5. Summary Ø Based on experimental conditions nucleophilic substitution reactions take place strictly by S N 1 or S N 2 mechanism or a mechanism borderlined between the two. Ø To explain the borderline mechanism, two theories were proposed that either a unifying intermediate ion pair mechanism is functional or in a reaction mixture both S N 1 and S N 2 run simultaneously. Ø Based on lifetime of intermediates the term borderline implies to the existence of a line separating S N 1 from S N 2. When the intermediate carbocations exist in energy wells having at least the time of a bond vibration ( 10-13 s) S N 1 mechanism follows which changes to the S N 2 mechanism if the energy well for the intermediate disappears. Ø The nature of substrates play central role in deciding mode of nucleophilic substitution. Whereas based on electronic and stearic factors it has been established that substrates with primary carbon undergo S N 2 mechanism, and tertiary carbon undergo S N 1mechanism whereas secondary carbon may chose to take either of the mechanism or might as well exhibit borderline mechanism. Ø Both inversion and racemization of products occurs in borderline mechanism. Ø Mixed kinetics with additive rate law is operative for borderline mechanisms. Ø For substrates with bridgehead carbon nucleophilic substitutions are difficult to take place. Ø Increase in the concentration of nucleophile speeds up the rate of S N 2 mechanism when both S N 1 and S N 2 mechanisms are operative and competing simultaneously. Ø Good nucleophiles drive competing reactions in favor of S N 2 mechanism Ø Polar protic solvents speed up rate of S N 1 mechanism by stabilizing the intermediates. Ø Polar protic solvents decrease the rate of S N 2 mechanism as they stabilize reactants better than the intermediate transition state.