research summaries f o r teachers WILLIAM R. DOLBIER, Jr.
organic chemistry
University of Florida Goinewille, Florida 32601
Neighboring Group Participation Solvolysis reactions constitute a very important and very highly investigated area of mechanistic organic chemistry. A very important group of solvolysis reactions, yet one which is usually slighted in introductory organic courses, is that where more than one functional group is near the reaction site. Such neighboring groups often interact with the reaction site, and such interaction usually results in dramatic changes in the course of the reaction. An example of such an interaction is the following reaction where the acetolysk of trans-2-acetoxycyclohexyltosylate, I, in the presence of acetate ions, leads entirely to trans-1,2-diacetoxycyclohexane, I11 (I).
an important artifact of reactions where NGP plays a significant role. Perhaps the most important reason for discussing NGP in some detail at the undergraduate level is the fact that molecular biochemistry is probably one of the most rapidly expanding fields of chemistry, and naturally-occurring organic compounds are almost invariably multifunctional species. Thus NGP is a very important factor in biochemical reactions. hloreover, NGP is, in itself, a very interesting and profitable area for discussion and follows quite easily on the heels of the discussion of the more conventional nucleophilic displacement reactions. Requirements for Participation
The only requirements for a neighboring group to lend anchimeric assistance are, first, that it have available either a pair of nonbonded electrons or a electrons and, second, that it he located in a position which enables it to interact with the baclc-side of the site which will bear the positive charge. There is much controversy as to whether rr electrons can be so utilized, and discussion of this type of interaction will be deferred to a future Research Summary. A general representation of neighboring group participation is shown below where k, is the rate constant for the reaction involving NGP and k , is the rate constant for the reaction without assistance.
I
d>cH3 -&r
(optically active)
rast
H
OCCH,
I1
II 0 III (racemic)
The complete retention of configuration at carbon 1 is explained best by invoking neighboring group participation (NGP) and the intermediacy of acetoxonium ion I1 whereby the carbonyl oxygen has ostensibly lent anchimeric assistance to the departure of the tosylate anion. Many aspects of NGP should be of real interest to students of organic chemistry. First, the kinetic nature of an assisted reaction is usually drastically different from that of an unassisted one. Secondly, the observed stereochemistry for assisted reactions is markedly different from that which one would expect for the unassisted solvolyses. Skeletal rearrangements are also often 42
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Journal of Chemical Education
G
I
/G+\
Cn-c
I X
products
kc
I c,-C+
+ x-
C,-c
+
X-
fast
products
The probability that ring closure will occur decreases as ring size increases, with a three-membered riug having the smallest decrease in entropy for riug formation. Of course three-membered rings have significant ring strain while five- and six-membered rings do not. Thus, the balance of entropy and enthalpy factors is such that three-, five-, and six-membered rings form most easily. I n theory, any neighboring group is capable of pro-
viding anchimeric assistance if, in forming such a cyclic transition state or intermediate, it can provide stabilization to the carbonium ion. I n general, the amount of assistance that can be provided by a group is related to its nucleophilicity; that is, W
--C
/O
'O-
>-C
WI
/O
OBs
'OH
It should be obvious that just because a group is nearby, it does not have to participate in a reaction. It only does participate when it is energetically advant* geous. It is also logical that if interaction of a neighboring group with a carbonium ion would be favorable, then interaction with the incipient carbonium ion should also be favorable. Thus, in those cases where it is stereochemically allowed, participation will be concerted with expulsion of the leaving group, and a significant lowering of transition state energy will generally be observed. There are many important consequences of these energetic and stereochemical requirements for NGP. The observation of these consequences is generally considered prima facie evidence for NGP in the reaction. It is important to be able to recognize both the strengths and the limitations of arguments of this kind. Kinetics
M of the data for the unsubstituted brosylate, IX, however, indicates that such conclusions should not be drawn so easily. The key to safe utilization of relative rate data is for one to be certain to choose a realistic model to compare with that system which one believes to be operating with NGP. One has to be certain that steric and electronic effects are alike in both systems; otherwise rates must be corrected for the differences. Steric differences are often difficult to estimate, and thus it is best to choose one's systems carefully so as to avoid the problem. I n the case of molecules of VII and VIII, for example, conformational preferences for each are quite different and such equilibria will affect the relative rates. In comparing the rates of VII and IX, it is obvious that one must first correct for the inductive effect of the acetoxy substituent. The presence of the electronegative oxygen linkage undoubtedly gives rise to a hindrance to ionization in compound VII. Such effects may be approximated in various ways (4). It should be emphasized again that relative rate data should be used with great care.
The kinetic requirement for NGP is such that the resultant onium-carbonium ion intermediate is more stable than that ion which would have resulted without NGP. Evidence for this extra stability can often be dramatically observed. I n the hydrolysis ofp, pl-dichlorodiethyl sulfide, IV, the first-order rate constant drifts downward as the reaction proceeds, thus indicating the presence of a common-ion effect. (2). The hypothetical primary carbonium ion expected from the simple SN1 ionization would never have the stability to permit such an observation. Thus the ethylene sulfonium ion, V, is invoked as the intermediate which gives rise to this effect.
As mentioned before, reactions involving NGP are generally quite stereospecific. Usually such interaction gives rise to products with r e t a t i o n of configuration as opposed to the normal racemization or inversion of the reaction center. Another classic example of this is shown below. In this case, the lactone XI, hypothesized as an intermediate, cannot be isolated, but there is much evidence for its existence(5).
Since the transition state energy with NGP is also Iowered relative to that without NGP, rates are affected, often dramatically, by such interaction. In fact, comparison of rate data is probably the most commonly used tool in investigating NGP. It is, however, a method fraught with pitfalls, and an investigator must be very cautious in interpreting relative rate data. In comparison of the relat,ive r a t e data for the acetolyeis of the compounds above ($), comparison of trans and cis compounds VII and VIII seems to provide excellent verification of NGP in the former case. Inclusion
An intermediate epoxide can be isolated in the conversion of bromohydrins to glycols under basic conditions (6). These intramolecular reactions are generally thousands of times faster than their intermolecular counterparts.
Stereochemistry
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a bridged carbonium ion, or a concerted rearranged cation could give rise to enhanced rates. The problem is perhaps best exemplified by the still controversial question of the existence of phenonium ions in the solvolyses of p-phenylethyl systems. The three possibilities can be depicted thus
xv
(meso only)
I n this reaction, because the intermediate has oxygen equally bonded to each carbon, oxygen will have undergone a 1,2-migration in half of the product. Such rearrangements are very common in reactions with NGP, and all of the succeeding examples in this paper have this characteristic. In the reaction below, the hypothesized symmetrical bromonium ion explains the observed results fully (7). The evidence for the bromonium ion intermediate is quite good and has been discussed elsewhere (8).
Rearrangement and stereospecificity as well as rate enhancement form the case for the phenonium ion (10).
xxn (optically active)
XXm (d,l mixture)
Looking again at the trans-2-acetoxycyclohexyl to& ylate system, it can be seen how the existence of the intermediate acetoxonium ion, 11, is clearly implied by the product compositions under various reaction conditions (1).
"d -y
0
XX
&+ 0
-
FCHa
&kHz
XXI
\ /OCHxCHs
XIX
Ortho-ester XIX can actually be isolated from the solvolvsis in anhydrous ethanol (9). The Question of Bridged Ions
Bridged intermediates need not always be invoked wherever anchimeric assistance is observed. Rate enhancement is consistent with various mechanisms. Formation of either a stabilized "free" carbonium ion, 44 / Journol o f Chemicol Education
11
OC-cH, 0
action system and its environment (IS),while the other prefers the hypothesis of two competing reaction modes, one anchimerically assisted and one anchimerically unassisted (solvent oarticioation), (1L). ., While being of considerable interest and value, this controversv cannot be dealt with in deoth here. However, in an undergraduate course it is often extremely stimulating to present such areas of controversy along with appropriate comments as to the validity of the various arguments. Such contact with the reality of
In
H
-
generality of their importance in solvolysis reactions. One school would like to hypothesize a "continuous specwill depend trum of cations" on the whose nature precise of the nature re-
C H ~ C H ~ H ~
0-H
H
0
11
I1
1
I n special systems the bridged system can even be isolated (If), and some phenonium ions have been directly observed in the nmr (18). schools of thouzht Nevertheless, there are concerninp. definitely two the
\
chemical problems is very important in a course which very often may appear cut and dried. Conclusion
(3) WINSTEIN,S., GRUNWALD, E., A N D INGRAAAM, L. C., J . Am. Chem. Soe., 70, 821 (1948). (4) STREITWIESER, A,, JR., "Snlvolyti~ Displacement Reactions." McGraw-Hill Book Cn.. Inc.. New York. 1962, p, 121.
While NGP is usually discussed a: some length in graduate organic courses, introductory courses are usually sadly lacking in such exposure. This paper is certainly not meant to he a thorough review of neighboring group participation but only an introduction to an area which I believe has great potential as a part of the undergraduate organic curriculum. Further examples and elaborations may he found in most advanced organic textbooks.
C o m n m , W. A,, I I u c ~ a s E. , D., AND INCOLD, C. K., J. Chem.Soe., 1208 (1937). WINSTEIN,S., A N D LUCAS,H. J., J . Am. Chem. SOC.,61,
Literature Cited
OLAH,G. A,, NAMBNWORTH, E., COMISAROW, M. B., AND RAMSEY, B., J. Am. Chem. Soe., 89, 711 (1967). BROWN, H. C., BERNHEIMER, R., KIM, C. J., AND SCHEPPELE, S. E., J . Am.Chem. Soe., 89, 370 (1967). YON R. SCHLEYER, P., A N D LANCELOT, C. J., J . Am. Chem. Soe., 91,4297 (1969); DIAZ,A. F., AND WINSTEIN, S., J. Am. Chem. Soe., 91,4300 (1969).
(1) WINSTEIN, S., HI:SS, A. V., A N D BUCKLRS, R. E., J. Am. Chmt. See., 64, 2796 (1942); WINSTI:IN,S., A N D I%ECK, R., J . Am. Chem. Soc., 74, 5584 (19.52). (2) B.\RTLWT,P. I)., .AND SWUN,C. G., J . Am. Chem. Soc., 71, 1406 (1949).
1576 (1939).
WINSTEIN, S.,
AND
LUCAS,H. J., J. Am. Chem. Soc., 61,
2843 (19391,
D ~ L B I E W. R , R., JR., J. CHEM.EDUC.,46, 342 (1969). WINSTEIN.S.. A N D BUCKLES. R. E.. J . Am. Chem. ~ o c . . 65,613 '(1943).
CRAM,n. J., J. Am. Chem. Soc., 86, 3767 (1964). BAIRD,R., A N D WINSTEIN,S., J. Amer. Chem. Sac., 85, 567 (1963).
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