California Association of Chemistry Teachers
Marjorie C. Caserio University o f California lrvine
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Reaction Mechanisms in Organic Chemistry I. The experimental approach
O n e of the most intriguing and challenging areas of chemistry is that which deals with the mechanisms of chemical react,ions. Historically, the development of our knowledge regarding the inner worlcings of reactions, particularly organic reactions, dates back to the turn of t,he century when it became possible (or rather it became the practice) to apply physical methods to the study of organic reactions. It is reasonably true to say that quantitative experiments in organic chemistry were rare indeed before 1900, probably because chemists were much too busy discovering new reactions and making hosts of new compounds to divert their efforts toward the study of known reactions in more depth. The change of approach in recent years is very evident, and it is now common practice to question how and why a reaction oeeurs-with the result that organic chemistry is no longer an endless catalog of reactions that can neither be rationalized nor correlated with anything except, the name of the man who discovered them. There are, in fact, suprisingly few general types of organic reactions, for all reactions fall into one or another of the
following categories: substitution, addit,ion, elimination, rearrangement, oxidat,ion, and reduction. An example of each type of reaction follows: CH.Rr
+ OH-
-
+ Br
C&OH
S~rbstit~~lion
CH,
\
C=O
/
+ HCN
-
CHa
CHs
\c/ CH!
-
OH
\CN
Addition
CHJCOCOIH
CHIC02H
+ CO
Elimination
=
CHx=CH-CHz-COIH CHBCH=CH-C09H Rearrangement
\/ OH
CH, CH!
H'
oxidation
CHI
\
reduelion
7"
CH, Osidation-Reduction
This simple classification, however, has lit,t,le or no connection with t,he mechanisms available to these reactions. One may well ask, then, t,he meaning of the t,erm "reaction mechanism," and what informat,ion is necessary to establish one. Briefly, a reaet,ion mechanism is a detailed descript,ion of the chemical transformation of reactants to products. More explicitly, a mechanism identifies the individual st,eps in the overall reaction arid the sequence in which they occur, and it describes the energy, composit,ion, stereochemistry, and electronic configuration of the tsarisition state for each step. The term transition state is a very important concept in describing the mechanism of a reaction and is defined as the configuration of reacting molecules a t the point of maximum energy in the eonversion of reactants to products. I t is represerit,ed diaerammat,ieallv in Figure 1 as the maximum in the
TRANS ITION STATE
PROGRESS
OF R E A C T I O N
Figure 1.
-
Energy diogrom of the reoction A B or o function of the energy of the .,..tern. me point of maximum energy corre. wands to the transition state. and the height of the energy .. barrier correrpandr to the energy of activation, AE..
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Journal o f Chemicd Education
Presented in part at. the Sixth S ~ ~ m m eCACT r Conference, Asilomar, California, Augwt 1964. A second paper on this topic will appear in the next iswe of THIS JOURNAI..
curve describing the progress of a simple reaction A + B, as a function of its potential energy. I n a complex reaction of several st,eps,there will he as marly transition states as there are steps; hut when only one transition state is referred to in a complex reaction, this generally means the point of maximum energy for the overall process. Ideally then, to establish a reaction mechanism, one needs to know the identity of all t,he participants in each step of the reaction; the sequence of the individual steps; the rate of each step; the relative energies of the reactants, transition states, intermediates, and products. Finally, the compositiori of each transition state should be known in enough detail to define the stereoohemistry and the manner and extent of hondbreaking in each t,ransformation. The manner of bond-breaking refers to the type of cleavage of an electron-pair bond, whether homolytic or heterolytic; lhree examples are shown below:
homolytic cleavage
hetemlytic cleavage
If t,he above information were available for a given reaction, the mechanism of t,hat reaction would be uniquely defined. Unfortunately, the discrepancy bet,ween what we need to know and what we actually know about any one reaction is very great, and it is unlikely t,hat we will ever be able to desrribe a reaction as complet,ely as necessary to rigorously establish its mechanism. Even so, much has been discovered conceniing t,he n~echanismsof organic reactions; the objective of this article is to describe briefly the experimental approaches that are used in their study. Examples have been chosen to illustrate the kinds of information that have been obtained from product st,udies,kinetic and stereochemical &dies, and isotopiclabeling experiments. A subsequent article will deal mainly with physical techniques for the detectiou of transient reaction intermediates. At this point, it is important to realize that it is not possible to prove a reaction mechanism by any available method. Mechanisms can be eliminated from
consideration, however, if they are shown to be inconsistent with the observed facts. Thus, reaction mechanisms become "established" by virtue of their plausibility and because they accommodate all the experimental data. Product Studies
The most obvious starting point in any reaction is to indentify the reactants and the products. While this information rarely indicates the mechanism of reaction, it does so in some instances. A subtle example of the value of product studies concerns the nature of the highly reactive species known as methylene, :CHz, formed from diazomethane on irradiation.
The question of interest concerning this reaction is whether it leads to met,hylene in which the two nonbonding electrons have parallel spins ( f t, i.e., triplet methylene) ( I ) , or antiparallel spins ( t i , i.e., singlet methylene). The answer is suggested by a study of Lhc photochemical decomposition of diazomethane in the presence of cis- or trans-2-butene ( 2 ) . Under these conditions, methylene adds to the double bond of the alkene, and the fact that cis-l,2-dimethylcyelopropane was formed from cis-2-butene, and trans-1,2-dimethylcyclopropane was formed from trans-2-butene, is more in accord with singlet methylene (CHz t l)as the reacting species than with triplet methylene (CHz lt).
The argument here is partly intuitive. Had the addition occurred through triplet carbene, reaction would necessarily have been stepwise for the reason that spin inversion must take place for a second carboncarbon bond to he formed. Since it is reasonable to expect spin inversion to complet,e favorably with rotation about the butene carbon-carbon hond, a mixture of cis and trans products should have been formed.
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Since mixtures of cis and trans products were not obtained, reaction probably involves the addition of singlet carbene, which may in principle add in one step, no spin-inversion being necessary. The argument has been greatly strengthened by experiments designed to produce triplet methylene and the demonstration that this species adds non-stereospeeifically to cis- and trans-2-butene (3). Although only one example of the value of product studies is quoted at this point, several more examples are noted in subsequent sections.
Mechanism 1
+
I,
H?O
fast
HOI
+
HI
Kinetic Studies
Among the oldest and most valuable techniques used in the study of reaction mechanisms is the kinetic method. By measuring the dependence of the rate of reaction on the concentrations of all the participants, a rate expression may be established which may suggest the composition of the transition state of reaction. Further, a study of the effect of temperature on the rate will give the energy of activation of the reaction, AE, of Figure 1. One of the earliest recorded studies of a reaction mechanism by kinetic methods was carried out by Lapworth in 1904 (4). He studied the acid-catalyzed hromination of acetone, and observed that the rate of reaction was proportional to both the acetone and t,he acid concentrations but was independent of the hromine concentration. CHaCOCHs
+ Brs ---+ CHaCOCHsBr + HBr HBr
Kate = k[CH.COCHa][Ht]
Lapworth reasoned that this kinetic result demands that this reaction be stepwise, and that the slow or ratedetermining step must come hefore reaction with bromine. Another way of stating this is to say that the transition state does not contain hromine. Lapworth considered the slow step to he the enolization of acetone (eqn. I), followed by a relatively fast reaction of the en01 with bromine (eqn. 2). CHI
\
C=O
/
CHI
CH*
+
\ C ~ H Bra CHI
CHz +-Hi
-
H "
= CHa
:=OH CHs
CHJ
/
\
+ H+*
(I)
CH2Br
14+ HBr
fast
/
CH,
Journol of Chemicol Education
A distinction between the two mechanisms can he readily made from a study of the products; substitution of the anilinium ion is expected to lead to nzeta-iodoaniline, whereas substitution of aniline should give mostly para-iodoaniline. The fact t,hat a high yield of para-iodoaniline was obtained is consistent with substitution of aniline by H201+. Kinetic Isotopes Effects
A less direct use of the kinetic method in the study of reaction mechanisms deals with the effect of structure on reactivity, which is more specifically discussed in the next section. The so-called primary kinetic isotope effect illustrates very clearly how even the most subtle changes in structure, such as suhstitut,ion of deuterium for hydrogen, can profoundly influence the rate of a reaction, and t,his effect and its magnitude has a direct bearing on the mechanism of the reaction. The argument is based on the simple fact that C-H bonds are broken more easily than C-D bonds (6) and, therefore, in a given reaction, the deuteriumlabeled compound is anticipated to react more slowly than the unlabeled compound provided that the C-D (or C-H) bond is substantially broken (or stretched) in the transition state for the slow step of the reaction. For example, in the oxidation of labeled and unlabeled benzhydrol, (C6H5)&DOH and (CsHs)2CHOH, the unlabeled compound reacted 6.6 times faster than t,he labeled compound (7).
(2)
/
While several investigators since Lapworth's time have modified and added to his original observations, his basic conclusions remain unchallenged. Frequently, the kinetics of a reaction may be accommodated hy several possible mechanisms. Other methods or more refined kinetic methods may therefore he necessary to indicate which of the mechanisms is the more plausible. For example, the iodination of aniline with molecular iodine in aqueous solution has been studied kinetically (6),and the dependence of the rate on the iodine, iodide, aniline, and hydrogen ion concentrations can be rationalized by two mechanisms, one involving attack of positive iodine (H201+) on aniline, the other by attack of hypoiodous acid (HOI) on the anilinium ion. 572
Mechanism 2
+ 2Mn0,-
(CaHs)2CHOH
OH-
dC8H5
kalko = 6.6
This fact, combined with the observation that the rate is satisfactorily expressed by the following rate equation, Rate
=
kI(C6H,),CHOH][MnO,-] [OH-]
leads to the conclusion that the C-H bond is broken in the slow step of the reaction and that this step, and those prior to it, involve the species, (C6Hs)&HOH, MnOl- and OH-. An acceptable mechanism follows, involving a rapid pre-equilibrium between henzhydrol and base to form the benzhydrylate ion (I), which is then oxidized by permanganate ion in a relatively slow step to form benzophenone.
It is therefore impossible to tell whether the ratedetermining st,ep involves reaction with the solvent or not. Two exdreme mechanisms for such reactions are possible, as was first demonstrated by Hughes and Ingold (IZ), who usefully described them as 8,l (subslitutim-nucleophilie-unimolecular) and SN2 (substitution-nucleophili~bimolecular). RX
slow
%
fast Ha0
R++X--ROH+HX
S N Mechanism ~
These results, however, do not make clear the exact nature of the oxidation step (eqn. 3); that is, they do not indicate whether the C-H bond is cleaved by ahstraction of hydrogen as a proton (H+), a hydrogen atom (H.), or a hydride ion (H:-). Decisive evidence on this point is lacking at this time (8). The absence of kinetic isotope effects can be equally informative. For example, in the nitration of aromatic compounds, wherein hydrogen attached to aromatic carbon is replaced by a nitro group, the attacking reagent (NOz+) does not discriminate significantly between hydrogen, deuterium, or tritium (9-11). Thus, in the nitration of benzene-d, the rates of substitution of hydrogen and deuterium were found indirectly to be very nearly equal (10). D
NO,
D
This result implies that nitration is a stepwise reaction since the C-H bond is not weakened appreciably in the ratedetermining step. The accepted mechanism of substitution that accounts for the lack of an isotope effect involves the addition of NO2+ to the aromatic carbon to form a cationic intermediate known as the benzenium ion followed by a relatively fast elimination of H + to give the product. Further evidence on the reality of the benzenium ion is discussed in the second art,icle of this series.
Structure and Reactivity.
The Solvolyris Reaction
Reactions in which the solvent is one of the reactants ( e . , solvolyses) are classic examples of situations where the kinetic form of the rate equation gives little or no information as to mechanism; therefore they have been studied largely from the standpoint of the effect of structure on reactivity. By way of example, the rate expression for hydrolysis of an alkyl halide, RX, is (to a first approximation) deceptively simple since the rate dependence on the water concentration is obscured by the fact that water is present in large excess. RX
+ H20 ----+
ROH
Rate = k [RX]
+ HX
RX
+ &O
+ROH
+ HX
SwZ Mechanism
The SN1mechanism is a stepwise process involving a slow ionization of the alkyl derivative followed by a rapid reaction of the carbonium ion, R+, with the solvent. Reactions of this type have been established from kinetic evidence showing that the rate depends strongly on the ionizing power of the solvent and on the structure of the alkyl group R. The greater the stability of the carbonium ion R+, the higher is the reactivity of RX. Further evidence comes from the observation that the carbonium ion, R+, can he intercepted by the addition of other reagents, such as azide ion, which can react with R without affecting the rate of disappearance of RX. Thus, the product composition can be radically changed without sensibly altering the rate of reaction. This circumstance is easily explained by the following stepwise process.
I n contrast, the SN2mechanism is a one-step process involving the rate-determining attack of solvent at carbon with simultaneous cleavage of the C-X bond. Reactivity in SN2 reactions has been observed to depend largely on the strength of the attacking nucleophilic reagent (e.g., addition of OH- markedly increases the rate of hydrolysis of RX) and on the steric requirements of the group R (e.g., the reactivity order CH3X > CH,CH,X > (CH,),CHX >> (CH3),CCH2X parallels the degree of steric hindrance at the carbon undergoing substitution). Furthermore, S N reactions ~ have been found to be highly stereospecific, every act of substitution leading to inversion of configuration a t the reacting carbon. This was elegantly established by Hughes and coworkers in a related displacement reaction (eqn. 4) using a combination of kinetic, stereochemical, and labeling techniques (18). The reaction of 2-octyl iodide with radioactive iodide ion was followed by measuring the rate of incorporation of la'I- into 2-octyl iodide. The rate of racemization of optically active 2-octyl iodide in the presence of iodide ion was also measured.
The fact that the rate of iodide exchange was equal to the rate of inversion of configuration means that every substitution leads to inversion. Volume 42, Number 10, October 1965
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573
UNSTABILIZED ION
:~~BILI~ED' ION i ....-.. L... : . , .; :
:,, .. ... :
:
;
I
I
. . ,I ,
.
:
;
: :
.. . ....:,.' ../ :
Returning to the topic of ionization reactions, the two aspects most studied in SN1reactions are the nature of the carbonium ion intermediates, and the nature of the dissociation process. Regarding the former, a great deal of effort has been expended in studies which seek to correlate the structure of the carbonium ion intermediate with reactivity. The results of this work show that structural features in the group R that stabilize the developing charge in the transition state for ionization greatly facilitate reaction. Thus t-alkyl derivatives (e.g., (CH&CCl), a-haloethers (e.g., ClCH,OCH,), and allylic compounds (e.g., CH2=CH-CH, C1) are very much more reactive in ionization reactions than are primary alkyl compounds (e.g., CH3CH2C1) because, in each case, the energy of the transition state is lowered and the carbonium ion is stabilized by inductive and/or resonance efferts, as illustrated in the energy diagram of Figure 2.
There are, however, many con~poundsthat are considerably more reactive in solvolysis reactions than seems reasonable on the basis of simple structural effects. For such compounds, enhanced rates have been ascribed to special steric effects in some cases, and to electronic effects in others. Regarding the latter, direct participation of electrons from neighboring groups
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REACTANTS
