C. J. M. Stirling Universitv Colleae of North Wales Rongor, Coernorvonshire, Greot Britain
I
I
Closure of Three-Membered Rings Some o l d beliefs a n d some recent facts
A number of widely held beliefs about the formation of three-membered rings are promulgated directly, or implicitly, in the literature and in a number of well known texts. In common with many other erroneous beliefs, the "facts" are asserted with a frequency which rivals only the rarity of their substantiation. Comments about ring closure reactions typically include the following Three-membered rings are known to be hard to form ("difficult to prepare") because low yields are obtained in reactions which should give them. Three-membered rings form slowly by comparison with other ring sizes hecause af the high degree of ring strain. Formation of three-membered rings is promoted by proximity effects. (The argument runs that the ends of the chain are nearer to each other in three-membered ring formation than far any other ring size and hence that formation of three-membered rings is favored on probability (entmpic) grounds.) The experimental facts are t h a t three-membered rings are sometimes formed very much more slowly than, for example, five-membered rings1 hut sometimes are formed very much more r a p i d l ~ .It~ is ironic t h a t the mixture of prejudice and assumption t h a t exists in this area seems to have inhibited the investigation of what is a n intriguing and important problem in understanding molecular he-
havior, because, in spite of t h e importance of ring closure reactions, remarkably few accurate kinetic d a t a are available (1). It is, however, characteristic of poor theories that, like nasturtiums, they thrive better when the experimental soil is had. Data are listed in Table l2 for reactions in which t h e rate of formation of three-membered and of five-membered rings by intramolecular displacement can be compared. T h e gradation from large to very small values of t h e k 3 / k 5 ratio is striking. Three aspects of the d a t a are notable 1) In a single type of reaction a three-membered ring may he formed at least 23,000 times as fast as a five-membered ring. 2) For all systems so far investigated in which the k r l k . ratio is substantially larger than unity, a cyclopropone derivative is the product. 3) Only thme systems which possess an electron-acceptive (-M) group attached to the three-membered ring show a k 3 / k 8 ratio of greater than unity, but a (-M) group attached to the ring in the product raises k a / k ~ratios for some systems [ef (6), (7),and (811 but not others [cf (9), (10). and ( l l ) ] .
What generalizations can he drawn from this data? What hypothesis can such generalizations lead to? It is convenient to compare three-membered rings with fivemembered rings simply because more data are available for five rather than any other ring size. >Referencesto specific systems are in the table.
Table 1. Ring Closure Rate Ratios in Intramolecular Nucleophilic Displacement
Substrate No.
Temp. Starting Material
1
p-MeOCeHb(CHz),OBs
2
OGHI(CHZ),B~
3
~-M~.CBH*SO~(CH~)~B~
Product
Conditions
M ~ ~ ( C H , O IB .~
A
PM~~C~~~SOZCH~ICH,~~., A
W)
kalks
Ref.
AcOH
75
167
(2)
MeOH
25
11W
(3,4)
t-Bu-OK-t-Bu-OH
55
100
(5)
100 (min)
(6)
4
(EtOC0)KH4CH2)nCI
IEtOCOl?Cv(CHJ.+x
t-Bu-OK-t-Bu-OH
25
5
PhCO(CH2),C1
P~COCH~ICHJ..,
NsOH-HzO-Dioxan
25
23,000
(7)
EtOH-H1O
55
1.36
(8)
EtOH-H20
30
114
(8)
Dioxan-Hz0
30
v. small
(9)
H20
25
1.18 X
(10)
t-BuOK-t-BuOH
30
v. small
(11)
*A
p-Me.CsH&CHz),Cl
~ M C W ~ ~ S ~ ( C CI HII,
7
p-Me.C.HnS(CHz),CHPh.CI
I/(CH?in p - M e G H , S C\H P h CI
8
EtS(CH2),,CI
E~~;(CHJ.
9
NHACHd,Br
I C H J ~ ~B; H ~
6
-
A+
(CH,).,NHPh
CI
C?
I C H J ~ ~ & H6, CHPh
12
p-MeGH+SOzNH(CH2),CI
844 / Journal of Chemical Education
A
p.MeG~,so~~,,(c~,i.
Table 2. Ring Closure Ratios and Bromide Chloride Ratios
The hypothesis, (6, 8, 11) tentatively advanced to account for these observations, is that three-ring closure is promoted by (-M) groups because overlap in the transition state between the a (or d ) orbitals of the conjugative group and the distorted, high p-character, ring bonds of the three-rina- svstem (13, 14) lowers the free enerm . -. of the transition state. If this hvnothesis is valid. it follows that bond formation in th'transition state must be considerable for the effect to operate. Estimation of the extent of bond formation in transition states is not a straightforward matter in this type of system. Bromide:chloride ratios have been used (15, 16) to indicate degrees of cleavage of the bond to the leaving group, and hence the degree of bond formation, in displacement reactions. I t has been suggested (8) that for strongly solvating solvents such as water, values near to unity for the bromide:chloride ratio should be obtained either for very small or very large degrees of bond extension. 2) are known only for two sysValues of k B r , ~ (Table , tems which yield cyclopropanes by known mechanisms. In the first, cyclization of w-halogenoalkyl sulfones [substrate (3)], the kalk5 ratio is substantial and is accompanied by an exceptionally small bromide:chloride ratio. This is, of course, consistent with the hypothesis. In the second system, for the ketones ( 5 ) , a very large kalks ratio is associated with a very low bromide:chloride ratio. This is an apparent further confirmation of the high degree of ring formation in the transition state. It has, however, been shown (17) that ionization of the ketone is rate-determining and it is not surprising therefore, that the bromide: chloride ratio is low. By contrast, bromide:chloride ratios are normal for aziridine formation and ka/k6 ratios are small. The deduction to be drawn is that the degree of bond formation is similar to that for an intermolecular displacement process and no special effects are operating.
A second corollary of the hypothesis is that attachment of coniueative mouns should selectivelv nromote formation o i tiree-membered rings. Any effect of a conjugative mouo. however. should be less for formation of aziridines and thiiranium ions than for cyclopropanes because the excess enthalpy associated with angle strain is less and ring-bond distortion is reduced. Formation of thiiranium salts makes an interestine- contrast to the formation of aziridines in this respect. Attachment of an additional conjugative group in the sulfur-containing system [cf substrates (6), (71, and (8))produces marked selective acceleration of three-ring formation but the activation parameters for substrate (77shows that the acceleration is produced bv alteration of the entropy term and not of the &thalpy term. (9) For the aziridines;&tachment of phenyl groups [substrates (10) and ( l l ) ] produces little effect on relative or, surprisingly, on absolute cyclization rates (12). Activation parameters for both systems (the only sets available for three-ring:five-ring comparison) undermine the assumption that formation of small rings is entropically favored. Entropies of activation in both systems are actually more negative for the three-ring than for the fivering systems. Clearly, the factors which control rates of ring formation in even the simplest systems are known very imperfectly. Perhaps the comments that have been made in this article may help to remove the calm assumptions that all is understood and stimulate further work on these simple but significant systems. Literature Cited I11 Cap0n.B.. Quon. Re". 18.45 119641. I21 Hock.R..and Winstein, S.. J. Amrr Chem Sor.. 79.310511957i. I31 Baird. R., and Winstein. S..J Ampr Chpm S a c , 85.561 (19631. I41 Baird, R., and Winstein, S.,J A m e i Chrm. Soe., 84,788 11962i. I51 Knipe, A. C.. andStirling. C. J. M..J. Cham. Soc.. B. 809.11961). I61 Knipe, A. C., andstirling,C. J. M..J Chem Soc.. B.67. (1968). (71 Bird. R..Griifithr. G. F..andStirling. C. J . M.. unpublishaduork. 18) Bird. R.. and Stirling, C. J. M.. J C h m . Soc.. Perkinll, 1221 (19731. (9) Bohmc. E..and Sell, R., Chem B e y , 8I.123I19481. 110) Freundlich, H.. andKmopelin, H.. 2.Phya. Chem., 122.39119261. (11) Bird. R.,Knipe. A. C..andStirling. C.J.M.,J Chsm Soc.. Perkinn, (12) Heine H. W.. Miller, A. D.. Banon. W.H.. and ~ r e i n e r R. , w.. J Sor.. 75.4773l19531.
1131 Walsh.A.0.. T r o w FomdnvSoc.. 45. L79.119491.
Volume 50, Number 12, December 1973
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