Reactive Intermediate Chemistry

(4-Me)-1-N3 obtained from the reaction of azide ion with (4-Me)-1-Cl in 50:50 (v/v) water/trifluoroethanol is formed by trapping of a liberated carbocation intermediate, and the remaining 30% is formed by a preassociation reaction mechanism.14 For the tertiary substrates X-2-Cl, values of ks0 k d are observed when X is strongly electron withdrawing ðs 0:34Þ. These substrates react with azide ion to form X-2-N3 exclusively by a preassociation reaction mechanism.16 The minimum observed selectivity of ðkaz=ksÞobsd ¼ 0:7 M 1 is consistent either with Kas ¼ 0:7 M 1 for formation of an encounter complex between azide ion and substrate, which then undergoes unassisted ionization to form a triple ion intermediate ðk10 ¼ k1, Scheme 2.4); or, with a smaller association constant and a small compensating rate increase from a formally bimolecular substitution reaction ðk10 > k1, Scheme 2.4).

The yield of the nucleophilic substitution product from the stepwise preassociation mechanism ðk10 ¼ k1, Scheme 2.4) is small, because of the low concentration of the preassociation complex (Kas 0:7 M 1 for the reaction of X-2-Y). Formally, the stepwise preassociation reaction is kinetically bimolecular, because both the nucleophile and the substrate are present in the rate-determining step (k10 ). In fact, these reactions are borderline between SN1 and SN2 because the kinetic order with respect to the nucleophile cannot be rigorously determined. A small rate increase may be due to either formation of nucleophile adduct by bimolecular nucleophilic substitution or a positive specific salt effect, while a formally bimolecular reaction may appear unimolecular due to an offsetting negative specific salt effect on the reaction rate.

2.2.3. Coupling and the Change to a Concerted Reaction Mechanism.

Further destabilization of the already unstable intermediate of a stepwise preassociation reaction (triple ion intermediate in the inner upper right hand corner of Fig. 2.3) will eventually result in the disappearance of the energy well for this intermediate. The question then is whether crossing the relatively sharp borderline that marks the disappearance of the energy well for the reaction intermediate is accompanied by the appearance of a concerted bimolecular reaction of the nucleophile with the substrate (kcon, Fig. 2.3 and Scheme 2.4). The factors that control the relative barriers to passage through the inner upper right hand corner of Figure 2.3 (k10 ) and through the interior of the diagram (kcon) are most appropriate for consideration by theoretical and computational chemists. However, the following simple model to describe these relative barrier heights provides a useful point of departure for more advanced discussion.24

The barrier to reactions in which two processes occur in a concerted (synchronous) fashion has been proposed to be approximately equal to the sum of the barriers to these individual steps in a fully stepwise reaction [(A þ B), Fig. 2.4(I)]

minus the sum of (a) Transition state stabilization that results from the coupling of these two processes in a concerted reaction [C, Fig. 2.4(II)]; and (b) Intramolecular interactions in the transition state for the concerted reaction, which may be either stabilizing or destabilizing [D, Fig. 2.4(II)].24 The advantage to coupling of two or more processes in a concerted reaction is normally small, with the exception of pericyclic reactions. Therefore, such coupled concerted reactions are usually observed only when the barrier to conversion of the reaction intermediate to product [B, Fig. 2.4(I)] is small or absent, so that any advantage to coupling results directly in a lowering of the barrier to the coupled concerted reaction relative to that for formation of the intermediate of the competing stepwise reaction.24

2.3. Crossing the Borderline between Mechanisms

2.3.1. Nucleophilic Substitution at X-1-Y. The sharp transition from a stepwise to a concerted nucleophilic substitution reaction of azide ion with X-1-Y occurs at about the point of the disappearance of the energy well for the carbocation in the triple ion intermediate. This transition is illustrated by Figure 2.4(III), which shows the reaction coordinate profile for the reaction of azide ion with (4-F)-1-Cl through a carbocation ‘‘intermediate’’ that is too unstable to exist in an energy well, and Figure 2.4(IV), which shows the profile for the coupled concerted reaction (kcon, Fig. 2.3), which passes over an energy barrier similar to that for the ‘‘stepwise’’ reaction. The observed barrier to concerted nucleophilic substitution of 1 M azide ion at (4-F)-1-Cl is roughly equal to that for ionization of this substrate,13 so that, for this substrate, any stabilization of the pentavalent transition state for the concerted reaction that results from the coupling of the two processes is offset by unfavorable steric interactions [ðC þ DÞ 0, Fig. 2.4(IV)].

The advantage to the coupling of bond formation and bond cleavage in nucleophilic substitution at X-1-Y depends on the ring substituent X, the leaving group Y, and the incoming nucleophile Nu.

1.The partial neutralization of positive charge at the benzylic carbon from partial bonding to the incoming nucleophilic reagent in the transition state for concerted bimolecular substitution at X-1-Cl (kcon, Fig. 2.3) decreases the barrier to formation of this transition state compared to that for the more cationic transition state for the stepwise reaction (k1, Fig. 2.3). The relative

stabilization of the transition state for the concerted reaction increases as the ring substituent X is made more electron withdrawing.13 This corresponds to an increase in the advantage to coupling for the concerted reaction (C, Fig. 2.4) with decreasing stability of the avoided carbocation intermediate of the stepwise reaction.

2.Nucleophilic substitution of azide ion at (4-Me)-1-Cl is zero order in the

concentration of azide ion [N3 ]; but, there is a strong bimolecular substitution reaction of azide ion with (4-Me)-1-S(Me)þ2 .13 This change in the kinetic order for the reaction of azide ion shows that the pentavalent transition state

Nu ¼ N3 , to X ¼ 3-Br for Nu ¼ AcO , and X ¼ 4-NO2 for Nu ¼ MeOH (Scheme 2.3).13 In all cases, the transition from stepwise to concerted bimolecular substitution occurs close to the point where the estimated rate constant for collapse to product of the triple ion intermediate containing the carbocation-nucleophile ion pair just reaches the vibrational limit (ki, Scheme 2.3).13 The breadth (range of X) of the region of minimum observed nucleophile selectivity for borderline nucleophilic substitution increases with decreasing nucleophile reactivity (Fig. 2.5). This ‘‘delay’’ in the appearance of concerted bimolecular substitution reflects the decreasing advantage to the coupling of bond formation and bond cleavage in the transition state for the concerted reaction with decreasing nucleophile reactivity.

2.3.2. Nucleophilic Substitution at X-2-Y. The small azide ion product selec-

tivity ðkaz=ksÞobsd ¼ 0:7 M 1 observed for the reaction of azide ion and solvent with X-2-Y when X is electron-withdrawing (Fig. 2.2) is consistent with formation of an

association complex between the substrate and azide ion (Kas 0:7 M 1) that is converted to the product X-2-N3 with little or no nucleophilic assistance. A change to strongly electron-withdrawing X results in the disappearance of the barrier to collapse of the triple ion intermediate to the azide ion adduct. However, a pentavalent transition state in the interior of Figure 2.3 fails to appear, even when the carbocation in the triple ion intermediate of the stepwise reaction no longer exists for the time of a bond vibration. Therefore, the barrier to nucleophilic substitution at X-2-Y by a coupled concerted reaction mechanism (kcon, Fig. 2.3) remains much higher than that for reaction through the inner upper right hand corner, even as the ‘‘corner’’ changes from a ‘‘well’’ for a reaction intermediate to a ‘‘flat plateau’’. This is because the transition state for the fully concerted reaction is destabilized by steric crowding (C þ D 0, Fig. 2.6).

These data and conclusions for the reactions of X-2-Y pose a problem in nomenclature. Stepwise reactions may be defined as those that proceed through an intermediate, and concerted reactions as those that proceed in a single stage that avoids formation of an intermediate. A simple division into just these two classes is possible, provided nucleophilic substitution reactions that proceed without formation of a discrete intermediate are defined as concerted, whether or not they exhibit bimolecular kinetics. We favor this inclusive definition of a concerted reaction, even though it leads to ambiguity about the concerted nature for some reactions. Consider the nucleophilic substitution of azide ion with the tertiary substrates X-2-Y in the case where the carbocation X-2þ cannot exist in an energy well in the presence of azide ion for the time of a bond vibration. The coordinate for this reaction runs along the inner upper edge of Figure 2.3, but the energy well for the triple ion intermediate of the stepwise reaction is now replaced by a ‘‘flat plateau’’, so that there is first full cleavage of the bond to leaving group and then formation of the bond to nucleophile, but no transition state stabilization from the coupling of these two processes that is implied by the term concerted. Jencks proposed that such reactions be referred to as ‘‘uncoupled concerted’’, which indicates that there is no reaction

56 CROSSING THE BORDERLINE BETWEEN SN1 AND SN2 NUCLEOPHILIC SUBSTITUTION

Figure 2.6. One-dimensional cross-sections of the 2D diagram in Figure 2.3 for the stepwise and concerted nucleophilic substitution reactions of azide ion with ring-substituted cumyl chlorides X-2-Cl, which take place in the inner part of the diagram. There is a large steric hindrance to formation of the transition state for the concerted reaction ½ðC þ DÞ 0& and the barrier to this reaction (right-hand diagram) remains higher than that for the stepwise substitution (left-hand diagram), even when there is no significant free energy well for the reaction intermediate (B 0).

intermediate but that energetically favorable coupling of the bond cleavage and bond formation processes is not observed.1

The change from a stepwise preassociation mechanism through a triple ion intermediate to an uncoupled concerted reaction occurs as the triple ion becomes too unstable to exist in an energy well for the time of a bond vibration ( 10 13 s). The borderline between these two reaction mechanisms is poorly marked, and there are no clear experimental protocols for its detection. These two reaction mechanisms cannot be distinguished by experiments designed to characterize their transition states, which lie at essentially the same position in the inner upper right hand corner of Figure 2.3. Only low yields of the nucleophilic substitution product are obtained from both stepwise preassociation and uncoupled concerted reactions, because Kas (M 1) for formation of the preassociation complex in water is small and there is no significant nucleophilic assistance for either reaction. Degenerate reactions detected using isotopically labeled substrates, such as the exchange of 18O between bridging and nonbridging positions during the solvolysis of alkyl sulfonates, are sometimes thought to provide evidence for formation of an ion pair intermediate in which the oxygens of the sulfonate leaving group become equivalent.7,27 However, such exchange reactions may also proceed by an uncoupled concerted mechanism for which there is no energy well for the putative ion pair intermediate.1,28 Picosecond and femtosecond kinetic methods have the potential to directly characterize carbocation intermediates that react faster than the

58 CROSSING THE BORDERLINE BETWEEN SN1 AND SN2 NUCLEOPHILIC SUBSTITUTION

offset the stabilization of this transition state that results from the coupling of bond breaking and bond formation [C < 0, Fig. 2.4(II)]. The result is significant net stabilization of this transition state from coupling, so that the concerted reaction is kinetically significant even when there is a substantial barrier to the addition of solvent (and possibly azide ion) to the carbocation intermediate of the stepwise reaction.

The transition states for the stepwise (k1, Fig. 2.3) and concerted (kcon) reactions of (4-MeO,X)-3-Y lie at distinct well-separated positions on the More O’Ferrall diagram and show different sensitivities to changes in solvent polarity, meta substituents X at the aromatic ring, and the leaving group Y. For example, in 50:50 (v/v) water/trifluoroethanol (4-MeO,H)-3-Cl reacts with azide ion exclusively by a stepwise mechanism through the primary carbocation intermediate (4-MeO,H)-3þ with a selectivity for reaction with azide ion and solvent of kaz=ks ¼ 25 M 1. However, two-thirds of the azide ion substitution product obtained from the reaction of (4-MeO,H)-3-Cl in the less polar solvent 80:20 acetone/water forms by concerted bimolecular substitution and only one-third forms by trapping of the carbocation intermediate (4-MeO,H)-3þ with a selectivity of kaz=ks ¼ 8 M 1.33 The preferred pathway for the reaction of azide ion with (4-MeO,X)-3-Y in 50:50 (v/v) water/ trifluoroethanol changes from DN þ AN to ANDN as the meta aromatic substituent X is changed from H to NO2.34 Finally, concerted bimolecular substitution of azide

ion at (4-MeO,H)-3-SMeþ2 is favored by ‘‘synergistic’’ interactions between the nucleophile and the leaving group,25,26 and this reaction is important even when

the transition state for the stepwise reaction is stabilized by the strongly ionizing solvent water.35–37

Destabilization of primary benzylic carbocations by electron-withdrawing aromatic ring substituents must eventually result in the disappearance of the energy well for this intermediate, in which case concerted nucleophilic substitution will be ‘‘enforced’’ in the sense that no stepwise reaction is possible. These concerted bimolecular nucleophilic substitution reactions are normally strongly coupled.38 However, the nucleophile selectivity calculated from the low yields of the azide ion substitution product obtained from the reaction of 4-Nþ2 in the presence of 2 M azide ion in water that contains 4% 2-propanol, kaz=ks ¼ 0:21 M 1, shows that there is little or no stabilization of the transition state for the concerted reaction from the coupling of bond formation and bond cleavage at this substrate,23 even though the 3,5-(bis)trifluoromethylbenzyl carbocation 4þ cannot have a significant lifetime in the presence of azide ion. Therefore, despite the minimal steric hindrance to substitution at the primary benzylic carbon and the instability of 4þ, both of which strongly favor the coupling of bond formation and bond cleavage and reaction of 4-Nþ2 by a concerted mechanism, no such coupling is observed. Here the bond to the weakly basic nitrogen leaving group is so labile39 that its cleavage occurs without any assistance from added nucleophiles. This reaction is

3. ALIPHATIC NUCLEOPHILIC SUBSTITUTION AT TERTIARY CARBON

3.1. Reaction Mechanism

The essential features of the mechanism for aliphatic nucleophilic substitution at tertiary carbon were established in studies by Hughes and Ingold.40 However, as chemists probed more deeply, the problems associated with the characterization of borderline reaction mechanisms were encountered, and controversy remains to this day about whether these problems have been entirely solved.41 What is generally accepted is that tert-butyl derivatives undergo borderline solvolysis reactions through a tert-butyl carbocation intermediate that is too unstable to diffuse freely through nucleophilic solvents such as methanol and water. The borderline nature of substitution reactions at tertiary carbon is exemplified by the following observations.

1.The rate constant for solvolysis of the model tertiary substrate 5-Cl is independent of the concentration of added azide ion, and the reaction gives

only a low yield of the azide ion adduct (e.g., 16% in the presence of 0.50 M NaN3 in 50:50 (v/v) water/trifluoroethanol].42 Therefore, this is a borderline reaction for which it is not possible to determine the kinetic order with

respect to azide ion, because of uncertainties about specific salt effects on the reaction.42

2.There is no detectable common bromide ion inhibition of the reaction of tertbutyl bromide in 90% acetone in water,40,43 or common chloride ion

inhibition of the reaction of 5-Cl in 50:50 (v/v) water/trifluoroethanol or methanol/water.42 There is also little exchange of 36Cl from Na36Cl into unreacted tert-butyl chloride during its reaction in methanol.44

Y

3.There is little scrambling of 18O between the bridging and nonbridging positions during the reaction of 18O-labeled tert-butyl p-nitrobenzoate in 80% acetone in water.45

4.Stepwise solvolysis of chiral substrates through a planar achiral carbocation reaction intermediate normally results in the formation of racemic products. However, the solvolysis of chiral tertiary derivatives 6-Y proceeds with either