California Association of Chemistry Teachers
Marjorie C. Caserio
University of California lrvine
I II
Reaction Mechanisms in Organic Chemistry I/.
The reaction intermediate
The reactions of organic chemistry are seldom elementary. Very often they are composites of several reactions proceeding in sequence beginning with the reactants and ending in the formation of the observed products. Along the way, one or more intermediate compounds may be formed that are generally unstable under the conditions of reaction and do not survive for a sufficient length of time to be detected directly. One of the objectives in the study of reaction mechanisms is to identify the various intermediates that are formed in complex reactions, and this paper will describe briefly the more important methods and techniques that have been used to this end. As a start, it will be helpful to explore the various situations that can exist in stepwise reactions by considering the hypothetical reaction of compound A going to compound B by way of intermediate X. A [XI B
- -
The energy profile of the overall reaction is shown diagrammatically in Figure l, wherein B is taken to be more stable than A by the amount of heat evolved in the reaction, AH. In order to get from A to B, however, an energy barrier must be hurdled, which leads to the intermediate X. The question is: what is X and how stable is it? On the latter point, three situations can be visualized. First, the intermediate may be stable enough to be isolated (i.e., point a of Fig. 1). Second, it could be an unstable intermediate 'with a short but finite life time (i.e., point b of Fig. 1); and third, it could be so short-lived as to be virtually indistinguishable from a transition state (i.e., point c of Fig. l), in which case it becomes difficult if not meaningless to try to differentiate between a one-step or twostep process. There are, of course, reactions which fall between the extremes of forming stable intermediates or high energy transition states, but we are concerned here principally with situations where a true Presented in part at the Sixth Summer CACT Conference, Asilomar, California, August, 1964. The first paper an thk topic s 42,570 (1965). appear in ~ m JOURNAL,
intermediate is formed and with the methods by which it may be detected. These methods encompass actual isolation, trapping experiments, and spectroscopic detection. Isolation Experiments
The existence of a reaction intermediate is generally inferred from kinetic data ( 1 ) ; but, since this kind of evidence is never conclusive, it is highly desirable to obtain more positive evidence. Ideally, we should isolate the intermediate, confirm its structure, and demonstrate that it gives the same reaction products under the same conditions and at a rate consistent with its reactivity in the overall reaction. This has proved possible in a number of interesting reactions where the intermediates in question are of moderate stability. For example, the rapid solvolysis of p-hydroxyphenylethyl bromide (I) in the presence of methanol and base to give the methyl ether I1 led Winstein and Baird (2a) to suggest that the spirodienone I11 is formed as an intermediate by participation of the electrons of the phenolate group in displacing the bromide ion.
By working under carefully controlled conditions, they succeeded in isolating the suggested intermediate (111) and showed that it reacted readily under the reaction conditions to give the methyl ether I1 (2b). The second example is concerned more closely with the mechanisms of electrophilic aromatic substitution. Based on kinetic evidence, substitution has long been Volume 42, Number 1 1 , November 1965
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accepted as a stepwise reaction involving the formation of a cyclohexadienate cation N (3). Until recently, however, no such ionic intermediates had ever been isolated.
mediate formation of the allenylcarbene, VI.
A number of these carhonium ion salts (benzenium
Part of the reaction very probably does proceed through VI; this was convincingly demonstrated by Hartzler (7), who succeeded in trapping the carbene intermediate by conducting the solvolysis of 3-chloro-3-methyl-lbutyne in the presence of styrene. Under these conditions, the carbene (VI) would be expected to add to the double bond of the alkene, and indeed a fair yield of the expected cyclopropane adduct VII was obtained.
or henzenonium complexes as they are often called) have now been prepared and have been shown to lead to products typical of aromatic substitution reactions such as alkylation, acylation, and nitration (4, 6). I n one case, Olah and Kuhn (4) isolated the benzenium complex V from the reaction of nitryl fluoride and homn trifluoride with trifluoromethylbenzene at low temperatures.
CH.
CH,
CFa
On warming to -50' and above, the salt decomposed quantitatively to give m-nitrotrifluoromethylbenzene, which is the expected nitration product of trifluoromethylbenzene. Trapping Experiments
Frequently, reactions proceed b y way of intermediates of such high reactivity as to preclude their isolation under physically attainable conditions. If such is the case, it may still be possible to substantiate their existence by diverting or trapping them by reaction with added reagents for which they may have a high affinity. There are several examples of the successful application of this technique; two are described below. Hennion and coworlters (6) investigated the kinetics of solvolysis of 3-chloro-3-methyl-1-butyne; and, from their observation that the rate of solvolysis was profoundly increased in the presence of base, they proposed that the reaction takes place through the inter-
&H,
VII, 48%
The mechanism proposed for the basic hydrolysis of a-haloalkynes, described above, is formally similar to that originally suggested for the amination of aryl halides with allcali amides (8). Both types of reaction are thought to involve an elimination-addition sequence. I n the amination of aryl halides, benzyne (VIII) was proposed as the intermediate (a), but all attempts to isolate it failed.
VIII
Benzyne, however, was anticipated to be very reactive towards dienes, and, this being so, could probably be trapped as a Diels-Alder adduct when formed in the presence of a suitable diene. This has been amply confirmed in several laboratories, notably that of Wittig and his colleagues (9),who showed that the dehalogenation of o-fluorobromobenzene with lithium amalgam led to benzyne which could be trapped in the presence of furan to give the expected adduct IX.
PROGRESS OF R E A C T I O N
Figure 1. Energy diegram describing the conversion of A to B via X. The shallower the minimum representing X, the less stable is X relative to A or 8.
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VIII
IX
Specfroscopic Methods
A popular and informative approach to the detection of transient reaction intermediates at the present time utilizes spectroscopic methods. I n this way, benzyne (VIII) has been detected in the gas phase by two different physical methods, electronic absorption spectroscopy (10) and mass spectrometry (11). I n both methods, benzyne was formed by thermal or photochemical decomposition of benzenediazoninm-2carboxylate (X), and in the absence of other acceptor molecules, the fate of benzyne is dimerization to biphenylene (XI).
X
VIII
XI
In the decomposition of benzenediazonium-2-carboxylate by flash photolysis (lo), the absorption spectrum of the gaseous fragments formed during the first 2&80 micro-seconds after the lamp was shut off could only reasonably be interpreted as due to benzyne itself. As the intensity of the benzyne spectrum diminished, the spectrum of biphenylene intensified. I n a related experiment, X was decomposed thermally on injection into the heated inlet of a high resolution mass spectrometer (11). The mass spectrum of the fragments was, as expected, time dependent, and gave peaks of mass 28 (Nz) and 44 (GOz)and two other peaks of mass 76 and 152. The peak at 76 was attributed to benzyne. The intensity of this peak diminished as that of the peak 152 (hiphenylene) increased, and corresponds to the disappearance of henzyne by dimerization to biphenylene. Of the other physical methods that have proved useful in the detection of reaction intermediates, nuclear magnetic resonance (NIMR) spectroscopy and electron spin resonance (ESR) spectroscopy are of singular importance. Both of these methods are of relatively recent development and are potentially very powerful. They are nondestructive, sensitive, and are often very informative about the nature of a particular species. Before describing in any detail the many applications of NMR and ESR spectroscopy, it may be advantageous to describe briefly the phenomena of nuclear and electron spin resonance (13, I S ) . Whether we are concerned with an atomic nucleus (e.g., 'H, lac,I T , I5N),or an electron, each may be regarded as a charged spinning particle in which the charge distribution is spherically symmetrical. As such, each gives rise to a magnetic moment which can assume two different orientations in an applied magnetic field (see Fig. 2). These orientations correspond to alignment of the
magnetic moment with the applied field (magnetic quantum number +'/2) or opposed to it (magnetic quantum number -I/,). The phenomenon of nuclear spin or electron spin resonance results from absorption of electromagnetic radiation by the magnetic particle in a magnetic field to effecttransitions between the possible magnetic spin states (Fig. 2). The energy differencebetween the two states, AE,is related to the frequency of the absorbed radiation u and to the strength of the magnetic field H by the equations: AE = hv = ( h u / 2 r ) H
where h is Planck's constant and y is a constant, called the gyromagnetic ratio, that is dependent on the properties of the particular magnetic particle. I n practice, absorption is generally observed by irradiating the sample a t a fixed frequency v and varying the strength of the applied magnetic field such that, at some field strength, the above equations are satisfied and resonance occurs. Protons come into resonance in the radiofrequency region (60 megacycles per second) a t magnetic fields near 14,100 gauss. Electron resonance requires radiation in the microwave region (10,000 megacycles per second) and magnetic field strengths around 3,600 gauss. Much of the utility of Nh4R spectroscopy is derived from the fact that nuclei of the same kind in different magnetic environments absorb a t slightly different magnetic field strengths. This results in a spectrum of resonance frequencies dependent on the environment of each nucleus. For example, isopropyl fluoride, (CH&CHF, has just two types of protons-six methyl protons and one methine proton. Accordingly, the proton spectrum of isopropyl fluoride (14) consists, to a crude approximation, of two well resolved peaks a t 1.23 ppm and 4.64 ppm of intensity 6 : l corresponding to the ratio of the number of different types of protons (see Fig. 3). Closer inspection of the spectrum reveals that it has fine structure. Each of the main peaks actually consists of two lines, and each of these lines is
14
Figure 2. Possible orientations and energy level= of a nuclear magnet of magnetic moment +'/sin an externol magnetic fleld. H.
12
10
8
6
4
2
P P ~
Figure 3. Schematic nuclear mognetis resonance spectrum of iropropyl fluoride (upper) and the lropropyl cation (lower). For further detail, see ref. (14).
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a multiplet of closely spaced lines, which (for simplicity) are not shown in Figure 3. This complexity comes about because of the interaction of one magnetic nucleus on another, and is known as spin-spin splitting. A detailed analysis of spin-spin splitting is beyond the scope of this article, and need not concern us too deeply at this point except to note that the fluorine nucleus is responsible for the major splitting, and is designated as Jarin Figure 3. NMR spectroscopy has been used profitably to observe carbonium ions directly in solution (15), and since carbonium ions are important intermediates in many organic reactions, the significance of observing them directly is obvious. It is necessary to point out, however, that the conditions under which carbonium ions are formed in NMR experiments are not the same as the conditions of formation in organic reactions. Some caution must therefore be exercised in extrapolating spectroscopic results to reaction media. Carbonium ions are often formed in solvolysis reactions of alkyl halides (I), but they are seldom present in sufficient concentration to be observable by NMR methods. Nevertheless, Olah and coworkers (14) have discovered that ionization of alkyl fluorides occurs when the fluoride is dissolved in excess antimony pent* fluoride.
Under these conditions, alkylcarhonium ions are relatively stable and can be observed by NMR methods. For example, isopropyl fluoride dissolves in antimony pentafluoride, and the proton spectrum of the solut,ion (Fig. 3) is vastly different from that of isopropyl fluoride (14). The splitting due to the fluorine nucleus in isopropyl fluoride is no longer evident, which indicates that the fluorine has departed as fluoride ion. The two principal resonance lines still have the intensity of 6: 1, hut the positions of resonance (i.e., chemical shift) are shifted significantly to lower magnetic fields than in isopropyl fluoride. The spectrum is entirely consistent with that expected for the isopropyl cation, (CH3)&H+, and the influence of the positive charge is reflected in the large chemical shifts, the methine resonance being shifted considerably more than the methyl resonance. A number of ot,her alkyl- and allylcarbonium ions have been observed by spectroscopic methods, but space does not permit us to discuss them in detail. A number of oxocarbonium ions of the type RCO+ Xhave been prepared and studied spectroscopically (16), and since salts of this type have been postulated as intermediates in Friedel-Crafts acylations, it is important to note that their ability to behave as acylating agents has been ably demonstrated (16).
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Similarly, allcylcarbonium ion salts have been shown to be extremely reactive alkylating agents (14). Electron spin resonance spectroscopy has been successfully applied to the study of moderately stable radical species such as triarylmethyl radicals, aryl radical anions, and some radical cations. Of more interest to us here is the application of ESR to the detection of free radicals encountered as unstable intermediates in chemical reactions. Detection of radicals of this kind is not easy because of their low concentration. To overcome this difficulty, it is common practice to form the radicals in a solid matrix so that they are physically trapped and can do nothing but sit around and be observed by the ESR spectrometer. The same objection exists here as in NMR spectroscopy: observation of an unstable species under conditions far removed from the conditions of formation by chemical reaction is very interesting, hut of questionable relevance. Of considerable current interest are the ESR investigations that have led to the direct observation of triplet carbenes, which are divalent carbon compounds with two non-bonding unpaired electrons (I). As such, they may be regarded as a special type of diradical, and are expected to give ESR spectra. As one example, diphenylcarbene (CSHS)&: has been prepared in a rigid glass a t 77'K by irradiation of dipbenyldiazomethane. h"
(CaH&CNz
(C,H&C:
+ Ns
The ESR spectrum of the carbene so obtained confirmed that the ground state of this molecule is the triplet state (17). This same species has been proposed as an intermediate in the photochemical decomposition if diphenyldiazomethane in solution (18) since, in the presence of cis- or trans-2-butene, nonstereospecijic addition occurred.
CHs
\
cH-cH
CHa \cH-H
Not all ESR work is restricted to rigid media. For example, several organic free radicals formed in hydrogen abstraction reactions by hydroxyl radicals have been detected in solution by ESR methods. A complicated flow system was used (19) so that the abstraction reaction would take place continuously in the resonance cavity of the ESR spectrometer. The hydroxyl radicals were formed from titanium I11 solutions and hydrogen peroxide, and on meeting a stream
of solution containing the organic substrate, reacted to give the organic free radical.
--
+ H202 Ti'+ + OH- + HO. HO. + CHaOH .CH20H + H20
TiJ+
The cycloheptatrienyl
radical,
CIH7,has been detected by this method starting with cycloheptatriene (20). The spectrum is of special interest in that it consists of eight equally spaced lines (Fig. 4) which virtually demands that the spin density of the odd electron he distributed equally over the seven carbon nuclei.
Figure
:;;
4.
Electron
'z;,"radical. cycy;:
hepiotrienyl
120bJ.
The eight-line spectrum can then be explained as the result of spin-coupling of the electron with seven equivalent protons. This is a strong indication that the cycloheptatrienyl radical is a planar resonance-stabilized radical, XII. Finally, a few words may he said concerning a rather specialized application of nuclear magnetic resonance to the study of organic reactions. Since many reactions occur in a time interval comparable to that required for transition between spin-states of atomic nuclei, NMR becomes uniquely suited for the study of rapid rate processes in molecules. There is opportunity here to quote only two examples that are pertinent. One example concerns the NMR spectrum of the 2-norbornyl cation, XIII, which has been reported recently (21). This cation is formed in the ionization reactions of 2-norbornyl derivatives, and there is a wealth of kinetic, stereochemical, and labelingdata toindicate that it is unusually stable yet undergoes several interesting rearrangements and may have an unusual structure (22). Thus, the spectrum of XI11 at room temperature consists of only one line, which means that as far as the spectrometer is concerned, all the protons are equivalent. This result is easily explained in the light of previous experiments involving the 2-norhornyl cation, which have established possibly three rapid rearrangements: a 3,2hydride shift (eqn. I), a 6,Zhydride shift (eqn. 2), and a Wagner-Meerwein rearrangement (eqn. 3). Each of these rearrangements succeeds only in turning one 2norbornyl cation into another.
Provided these rearrangements are rapid, which they are a t room temperature, the protons are changing identity fast enough to become magnetically indistinguishable. On cooling the sample, however, the spectrum gradually changes until, a t -60°, three signals in the ratio of 4:6:1 are clearly evident. KO further change of any significance occurs in the spectrum on cooling, even as low as -143', hut warming to room temperature restores the single line spectrum. Evidently, the 3,2-hydride shift is relatively slow and, at -60°, the four protons at the 1, 2, and 6 positions; the six protons a t the 3, 5, and 7 positions; and the single proton a t the4 position are separately observable. The fact that the 6,2-hydride shift and the WagnerMeerwein shift are not slowed even slightly a t temperatures as low as -143" means that they are exceptionally low energy processes. The point has repeatedly been made, however, that the Wagner-Meerwein rearrangement of eqn. (3) is unreal, and that the 2-norbornyl cation is actually a hybrid structure with the positive charge delocalized over two centers, as in XIIIA. A low-energy route for the 6,2-hydride shift may well be via the symmetrical ion XIIIB suggested by Roberts (23) in which the hydrogen is partially bonded to three centers.
XIIIA
IL .'-H,' I XIIIB
The concluding example concerns the thermal isomerization of henzofurazan oxides by way of o-dinitrosobenzene intermediates (24, 25). According to structure XIV for 3,6-dibromobenzofurazan oxide, there are two closely similar but nonequivalent protons in the molecule; this is confirmed by the fact that the compound gives a, four-line NMR spectrum.
XIVA
H
I
H,C I CH+
'c'
slow
,
-+
XIIIA
A
Br
Br
XV
XIVB
As the temperature is raised, however, the spectrum changes until a t 50" it consists of a single line corresponding to two equivalent protons (26). On cooling, the spectral changes are reversed. A very attractive explanation of these results regards the thermal process as a ring-opening reaction to give the symmetrical dinitrosobenzene XV as a transient intermediate, which can revert equally to XIVA or XIVB. If this equilibrium is established rapidly enough, as it is at 50°, the ring protons become essentially equivalent on an NAIR Volume 42, Number 1 I , November 1965
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time scale. This equilibrium undoubtedly explains w h y it is that only o n e of t w o possible isomers of unsymmetrically substituted benzofurazan oxides are usually isolated, t h i s isomer presumably being the most stable thermodynamically.
Litemture Cited CASERIO, M. C., J. C ~ MEDUC., . 42, 570 (1965). (a) WINSTEIN,S., BAIRD,R., J. Am. Chem. Sac., 79, 756 (1957); (b) WINSTEIN,S., r n BAIRD, ~ R., J . Am. Chem. Sac., 79, 4238 (1957); 85, 567 (1963). For an authoritative account of electrophilic aromatic substitution, see BERLlNEn, E., +n "Progress in Physical R, Organic Chemistry," COEEN, S.G., ~ T R E ~ W I E S EA., TAIT, R.W., Editors Interscience, New Yark, 1964, Vol. 2, pp. 253321, See also OLAH, G. A,, ET AL., J. Am. Chem. Soe., 86,1039 (1964) and subsequent papers. OLAH,G. A,, AND KnaN, S. J., J. A n . Chem. Sac., 80,6535, 6540 (1958); OLAE,G. A,, ET u.,J. Am. Chem. Sac., 86, 2203 (1964). DOERING, W. YON E., ET AL., Tetmhedrn, 4,178 (1958). HENNION, G. F., AND NELSON,K. W., J. Am. Chem. Soc., 79, 2142 (1957); HENNION, G. F., AND MAWNEY, D. E., J. Am. Chem. Sac., 73, 4735 (1951). HARTZLER, H. D., J. Am. Chem. Sac., 81,2024 (1959). ROBERTS. J. D.. ET AL., J. Am. Chem. Soc., 78,611 (1956). W I ~ I GG., , AND POBIER, L.,Angew. Chem., 67,348 (1955); Ber., 89, 334 (1956). BERRY.R. S.. S P O ~ SG.. N.. AND STILES,M., J. Am. Chem. sm.,'84, 3570 (1962). BERRY,R. S., CLARDY, J., AND SCHAFER,M. E., J. Am. Chem. Sac., 86, 2738 (1964).
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(12) For further brtckground in XMR, see RoBEnTs, J. D., J. CREM.EDUC.,38, 581 (1961); MARTIN,J. C., J. CHEM. EDUC.,38,286(1961); and ROBERTS, J.D., Angew. Chem., Intern. Ed., 2 , 53 (1963). (13) For further background in ESR see V m ~ r nASSOCIATES, "NMR and ESR Spectroscopy," Pergamon Press, New York, 1960. (14) OLAH,G. A., ET AL.,J. Am. Chem. Soc., 86, 1360 (1964). (15) See DENO,N. C., an "Progres~in Physical Organic Chemistry," COHEN,S.G., STREITWIESER, A,, T m , R. U'., Editors, Interscience, New York, 1964, Vol. 2, pp. 129191. (16) OLm, G. A., ET AL., J. Am. Chem. Sac., 85, 1328 (1963). R.,W., ET AL.,J. Am. Chem. Sac., 84,3213 (1962). (17) M ~ R A Y (18) C ~ o s s ,G . L., AND CLOSS,L. E., Angew. Chem., 74, 431 11962). ~-..-,~
(19) DIXON,W. T., AND NORMAN, R. 0. C., J. Chem. Sac., 3119 (1963). . 99 (20) (a) ~ A R R I N G I T O N ,A,, A N D SMITH,I. C. P.,M01. P h y ~ 7, (1963); (b) WOOD,D. E., AND MCCONNELL, H. M., J. Chem. Phys., 37, 1150 (1962). P. YON R., ET AL.,J. Am. Cham. Soc., 86, 5679 (21) SCHLEYER, M., SCHLEYER, P. VON R., and OLAH, (1964); SAUNDERS, G. A,, J. Am. Chem. Soe., 86, 5680 (1964). (22) For an account of carbonium ion rearrangements in bridged hicyclic systems see BERSON,J. A,, in "Molecular Rearrangements," DE MAYO,P., Editor, Interscience, New York, 1963, Chap. 3. J. D., LEE, C. C., A N D SAUNDERS, W. H., JR., (23) ROBERTS, J . A m . Chem. Soc., 76,4501 (1954). F.B., AND WOOD,C. S., Prac. Nat. Acad. Sci. (24) MALLORY, U S . , 47,697 (1961). A. R., ~ K S N E S.,, AND Hmms, R. K., Chem. (25) KAT~ITZKY, Ind. (Lndon),990 (1961). F. B., private communication. (26) MALLORY,
