Lloyd N. Ferguson California State College at Los Anaeles Los Angeles, 90032
I
Ring Strain and Reactivity of Alicycles
I t was pointed out in a recent article that organic chemists have had a "field day" in alil cyclic chemistry over the past 10-15 years (1). One of the areas which has attracted extensive and continuing interest is the behavior of strained rings. Three facets of special attraction have been: rearrangements-thermally, photolytically, or acid catalyzed; electrical and magnetic forces between nonbonded groups; and effects of ring strain on chemical reactivity. The present article is obviously directed toward this third feature. Reactivity versus Ring Size Organic chemists have long recognized that intramolecular forces of various types have a profound influence on the chemical and physical properties of molecules. I n the case of alicycles, particularly important are bond angle and torsional strains and nonbonded interactions. In addition, there may exist dipole-dipole forces between polar substituents, intramolecular hydrogen bonds when appropriate groups are present, and delocalization effects in unsaturated and fused-cyclopropane systems. Heats of combustion data have shown that ring strains of cyclanes are very large for the small rings, pass through a minimum for the normal rings, reach a plateau with the mediumsize rings, and fall off sharply for the large rings (see Table 1). Interestingly, ring-strain energies are usually additive, e.g. (all figures lccal/mole)
and
although, bioyclobutane is an exception
One of the first modern-day correlations of ring strain with reactivity was made by H. C. Brown (2). He expressed the total cumulated ring strain as internal strain, I, and related the reactivity of cyclic derivatives to the change in I upon passing from the initial to the transition state. For a reaction of the SNl type, the change in coordination about the reacting carbon is 4 46
/ Journal of Chemical Education
Table 1. Comparison of Ring Strain and Ring Size of Cyclones Ring size of
oyclane
Total ring strain kcal/mole
Ring sise of oyolane
Total ring
strain kcd/rnole
to 3, and in an SN2reaction, the change is 4 to 5. I n both cases, the carbon bonds strive to achieve a planar trigonal orientation with bond angles of 120". This is hard for carbons of small rings, hence, the rings are relatively unreactive, whereas they exhibit a high reactivity for the reverse process, i.e., C.,+ ' C.,' I n the medium-rings, the major strain is from nonbonding repulsions, for example, between C1, C4, and C7, and between C2, C6, and C9 in cyclodecane, which is a maximum in the saturated compound.
Cyclodecane Conversion of a tetrahedral carbon to a trigonal carbon removes two of the H,H interactions and reduces transannular strain. Accordingly, these rings should have a ., + C,+ reactions and a low high reactivity for SN1C reactivity for the reverse process. For example, cyclooctanone does not add HCN (C,,. + Can,). These expectations just rationalized are expressed graphically in the figure, and they agree quite well with experimental observations. For illustration, the relative rates of acetolysis of cyclanol tosylates (3) and of ethanolysis of cycloalkyl chlorides (4) follow curve (a) of the figure whereas the log K/Ko (KOfor acetone) ratios for acetal and cyanohydrin formation of cy-
10) Predicted reactivity profiler for olicycler
clanones (6) and the rates of reaction of cyclanones with diazomethane (6) and borohydride follow curve (b) of the figure. An empirical correlation of reactivity with ring size was made of the rates of solvolysis of some neopentyl p-nitrobenzoates (7). Related to this, is the use of organic azides as a diagnostic probe for strained double bonds.
As the rings get smaller and internal stresses increase, the rates of reaction increase and the major solvolytic product changes from I1 to 111. A linear correlation was observed between the log of the relative rates and the strain released upon reaction, based on the combined hydrocarbon ring strain of the two fused rings in a given molecule. We have already noted that the strain of fused rings is approximately additive. An empirical correlation of chemical reactivity with bond angle strain was noted by Foote (8). Since v , ~ has been shown to be related to the C-CO-C hond angle and solvolysis rates of saturated tosylates should
Bond dissociation energies of cyclanes also reflect their ring strain (11).
Semiquantitative calculations have been made of strain energies in molecules which correlate well with rate and equilibrium data (1.9). In one study, Garhisch measured the relative rates of diimide reductions of a variety of olefins with respect to cyclohexene.
be a function of C-C-C hond angles, it was anticipated that there should be a correlation between vd and nonassisted solvolysis rates of secondary tosylates. log k(rel. ta cyclohexyl) = -0.132(vCa
- 1720)
Hence, k&one carhonyl frequencies not only provide a convenient measurement for estimating bond angles hut also serve as a useful method of predicting solvolysis rates. Moreover, by providing an estimate of the strain contribution to rates of solvolysis, the effects of electron delocalization may be assessed in similar unsaturated systems where both effectsoccur. Schleyer (9) extended the Foote relationship by adding terms for nonbonded interactions, induction, and torsional strain. However, since a good correlation is observed based on vd alone, bond angle strain must he the major factor affecting the rates. I t is to be kept in mind that reactivities are also influenced by the conformation of the leaving group. This may be the result of anchimeric assistance, nonclassical resonance stabilization of the transition state, or steric hindrance to ionization of the leaving group. Not only are single atoms in strained rings unusually reactive but also carbon-carbon bonds. The addition reactions of cyclopropaue, for instance, are well documented. Similarly, "zero bridge" bonds in strained polycyclic rings are prone to addition reactions.
Interestingly, bicyclo-butanes and -pentanes add electron-deficient carbon-carbon bonds from the underside of the folded molecules via a diradical intermediate
He also calculated rates of the reaction from activation energies based on the differences in strain energies of ground and transition states. The calculations showed that the reactivities are primarily influenced by torsional and bond angle bending strain. The trend in relative rates with ring size (Table 2) follows somewhat Table 2.
Comparison of Relative Reactivity Rates and Ring Size
Rel. rates of diimide reduction Observed Cdculated
Ring size
-.
12 Norbornene Bicyclo[2.2.2]octene
the reaction rate profile for elimination reactions proceeding by a syn-planar mechanism (IS). The high reactivity of norborneue and hicyclo[2.2.2]octene reflect the large torsional strain in the ground states which are relieved as the reactions proceed to the transition states. Reactivity of Small Rings
The behavior of highly strained small ring compounds has been especially fascinating, and most of Volume 47, Number I , January 1970
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47
their chemistry has been learned just in the past decade. A review of their preparation and properties is beyond the scope of this article. Chosen for this section is a discussion primarily of the reactivity of strained-ring carbons with special attention given to three-membered rings. The large strain energy in monocycles was noted above. For comparison, the strain energies in some Table 3.
Strain Energies in Some Small and Bridged Ring Molecules ( 1 4)
Comoound
Total strain (kcal/ mole i
Com~ound
1(13C-H) Coupling Constants For Some Small Ring Protons (15)
Table 4.
Compound
J('3GH) Hz
202
H Ref.
Total strain (kcall mole)
bi- and poly-cyclic rings are given in Table 3. One property of hydrocarbons closely related to bond angle strain is the s character of C-H bonds as reflected by acidity and J(13C-H) values, %s = 0.20 J(I3C-H), from which it is shown that the s character of many C-H bonds in strained molecules is equal to that in olefinic =C-H bonds (see Table 4). The greater the strain on the carbon, the larger is the s character in the C-H bond and the more acidic is the proton. For instance, bicyclobutanes readily react with butyllithium whereas bicyclo[2.1.0]pentanes require a stronger base such as amylsodium. Quantitative relationships between kinetic acidities and J(13C-H) have also been observed by measuring the rates of reaction of hydrocarbons with methyllithium (16) and the rates of tritium exchange in the presence of N-tritiated cesium cyclohexylamide (CSCHA) (17) (see Table 5). Beyond dyclohexane there is little change in acidity or in lac-H coupling. The change in s character and, hence, electronegativity of the C3 to Cs cyclane carbon atoms is also qualitatively shown (Table 6) by their rates of hydrogen abstraction by chlorine atoms or t-butoxy radicals (IS), and in the rates of enolization of cyclanones (19). Cyclopropane has drawn a large amount of attention, probably owing to the olefinic character of its carboncarbon single bonds. The recent literature abounds with reports on cyclopropane derivatives, part,icularly concerning the delocalizing ability ( I , 20) and photolysis (21) of t,he C3 ring, cyclopropenium ions ( B ) , cyclopropanones (M), cyclopropanols ($4, gem-dihalocyclopropanes (25), cyclopropenes (26), fused-ring cyclopropanes (BY), and protonated cyclopropanes (ZS), among others. Once more, we will limit our scope, and the topic chosen here is the general behavior of certain cyclopropane species, namely, the cyclopropyl and
(is).
48 / Journal o f Chemical Education
% i, chara~ter
40
Compound
J(W-H) He
% s character
Table 5.
-
Relative Kinetic Acidities of Some Hydrocarbons (16, 17)
log k,*l = 0.129 ( J W - H
log k/ko = 0.16 ( P G H - 32)
kd Hydrocarbon
J('8C-H) Hz
k,,
(toward MeLi)
Cyclane
cyclopropylcarbinyl carbonium ions, carbanions, and radicals
-
I>@rearrange
r)_e
7
De Do
S
V
O
b
rearrange or invert racemize fast
~artiallvrearranee
be ring opens
rapidly
Po ring opens rapidly
C~clopropyl Carbonium Ions. Cyclopropyl corn~ounds. like vinvl halides. are known to resist nucleo* philic s"bstituti&. For cxample, cyclopropyl tosylate times as fast as cyclohexyl tosylate solvolyzes and yields ally1 acetate. This inertness has been attributed to the greater electronegativity of the carbon atom in the strained ring, the delocalization of the C-X electrons, and the increased bond angle strain in going to a planar transition stat,e. Furthermore, carbonium ion reactions of cyclopropyl derivatives generally lead to ally1 rather than cyclopropyl products. Several studies have suggested that the transition state resembles IV and that solvolysis of cyclopropyl derivatives is facilitated by C2-C3 bond assistance through ring opening and delocalization of the positive charge by groups attached to CZ or C3 (34). i-
N
I n this respect, cyclopropyl groups are very effective in delocalizing posit.ive charge, and a simple example of this is found in the following relative rates of solvolysis of cyclopropyl bromides (29).
361
k,l(EtOH,,)
1.0
40
(trans)
1180 (trans)
- 15.9)
J("C-H) Hz
Table 6.
(toward C,CHA)
Relative Rate of Reaction per CH2
Toward Chlorine
Toward t-Butylhypochlorite
1.0 0.95
1.0 0.89
0.84
0.51 0.01
-
Cs
cs ca Ca
0.05
or alkylsodium reagents reacts to give products with over-all retention of configuration (SO).
The optical stability of the carbanion is reduced when groups are attached to the C1 atom which may delocalize the charge. Cyclopropyl Radicals. Cyclopropyl radicals have been generated by a variety of reactions, such as photochemical or thermal chlorination, vapor phaqe nitration, brominative decarboxylation, decomposition of cyclopropanecarboxylic acid peroxides, decarbonylation of cyclopropanecarboxyaldehydes, and possibly Kolbe electrolysis. I n most instances, particularly a t temperatures below 175-ZOO0, the cyclopropyl radical does not suffer ring opening. However, unlike the carbanions, cyclopropyl radicals racemize rapidly. For illustration, racemic VI is recovered when optically pure V is decomposed in hydrogen atom-donating solvents (&Ha,THF, etc.). Decomposition of V in CC14leads to racemic VII (51).
7340
(trans)
Cyclopropyl Caybanion. These ions, like vinyl carbanions, are more stable than alkyl carbanions and maintain their stereochemistry. Thus, the cycIopropy1 carbanion derived from organolithium, magnesium, Volume 47, Number 1, January 1970
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49
Similarly, cis and trans silver 2-methylcyclopropanecarhoxylates undergo brominative decarboxylation to give the same ratio of cis and trans'2-methylcyclopropyl bromides (52).
cis or trans
66%
unrearranged structure in strongly acidic solutions. The presence of additional cyclopropyl groups on the carbinyl carbon further stabilizes the methyl cation. For example, tricyclopropylmethyl p-nitrobenzoate hydrolyzes 10' times as fast as the triisopropylmethyl ester (5.5). Cyclic and fused-ring cyclopropylcarbinyl or homoallyl derivatives appear to react via ions analogous to VIII or IX. For instance
34%
The implication here is that the intermediate cyclopropyl radical is either planar or inverts very rapidly. From other work, it is believed that vinyl and cyclopropyl radicals are bent and possess inversion frequencies of 10~101° seo-'. Cyclopropylcarbinyl Cation. Cyclopropylcarbinyl compounds solvolyze rapidly to give the corresponding substitution products plus cyclohutyl and homoallyl derivatives.
\OTS 20%
68%
OAc
'
The structure of the intermediate ion or transition state continues to be a point of considerable debate (SS), although an accumulating body of evidence supports the notion that the transition state has a bisected structure VIII or a symmetrical homoallyl structure IX,
'OAc 6%
1%
Cyclopropylcarbinyl Carbanion. Cyclopropane rings bearing a nucleophilic w atom, whether carbon or other atoms, readily undergo 'ring-opening. For illustration, cyclopropylcarbinyl-magnesium or -lithium compounds exist largely in the form of the corresponding homoallyl structures (57).
.D - c H u, ~
&
CH,=CH-CH,-CKMg CH,=CH-CH,-CH*Mg
Similarly, cyclopropylamines and cyclopropanols suffer ring cleavage in the presence of strong bases.
NR CH,
in which all four carbons share the positive charge. The ion can be generated by a variety of processes, each of which may give all or part of the same product mixture. For example, the anodic oxidations of cyclopropaneacetic, cyclohutane-carboxylic, and allylacetic acids produce the corresponding carbonium ions which undergo substantial, but not complete, equilibration prior to being- trapped as the alcohols or - esters (54). Cyclopropylcarbinyl chloride solvolyzes in aq. &hand as fast as 0-methvlallvl chloride. .~ - - ~ ~40 - - times ~ " " This unusual rate, the S N character ~ of the reaction, the large salt effect, the rate enhancement by methyl substitution at all positions including the carbinyl carbon, the greater effect of groups a t the 3 and 4 positions than the 2 position, and the formation of ethers from solvolyses or deaminations in alcohol solvents are all indicative of a highly stable carbonium ion intermediate. Isotopic labeling shows that the ring carbons are completely equilibrated in the cyclopropylcarbinyl cation but the carhinyl carbon does not become equivalent to any of the ring carbons. Tertiary cyclopropylcarbinyl cations are more stable and are shown by nmr spectroscopy to maintain an ~
50
/
-" LiAIH.
//""\ CH,
NHR CHs
f l -
The interconversion of the cyclopropylcarbinyl and homoallyl carbanions depends upon the ionic character of the or ezo bond. Thus, the respective phosphorus ylides do not give crossed products (38).
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Journal o f Chemical Education
Cyclopropylcarbinyl Radicals. Such radicals have been generated by several reactions such as the freeradical chlorination of methyl cyclopropane or dicyclopropyl, by decarbonylation of cyclopropylacetaldehydes and by the radical additions of CCll or BrCCh to 2-cyclopropylpropene. Like the cyclopropylcarbinyl cations and anions, the radicals also suffer rapid ring opening. The proportion of products from the interconverting radicals depends upon the substituents present. I n the case of simple compounds, the homoallyl system is favored and only traces of the cyclopropane
products may be recovered. The presence of aryl groups, however, may stabilize the cyclopropylcarbinyl radical. Thus, a mixture of the two radicals X and XI, generated by the thermolysis of either tbutyl peracetate precursor, produces a substantial amount of the dipbenylcyclopropyl hydrocarbon in addition to the l,l-diphenylbutene (3g)).
Example of (3)
Strain in Special Groups
Unlike the cyclopropylcarbinyl carbonium ion, which interconverts with the cyclobutyl and homoallyl cations, cyclobutyl radicals apparently are not formed from cyclopropylcarbinyl radicals. A second dissimilarity with the carbonium ion specie, is the observation that a second cyclopropyl group on the carbinyl carbon has only a small stabilizing effect. Cyclopropylmethylene. Cyclopropylmethylene does not suffer ring cleavage like the corresponding carbanion. However, its ring stability depends upon its source. High energy sources, such as the photolysis of cyclopropyldiazomethane or cyclopropane plus energetic carbon atoms, yield principally ring fragmentation products.
On the other hand, the base-catalyzed decompositions of tosylhydrazones undergo fragmentation, ring expansion, or insertion, depending mostly upon the position of the cyclopropane ring relative to the carbenoid carbon (40). Major reaction (1) simple cyelopro-
.,
pylcarbinyl
Minor reaction
ring expansion fragmentation
(2) bicvclio cvclo"
g;~[lCar-
fragmentation
(3) bioyoii'c 8-oyclouro~vlearbe&" insertion Example of (I)
Example of (2)
insertion
We saw in the previous section that small rings have large bond angle strain. Related to this has been an interest in determining how small a ring may be prepared containing an acetylenic or cumulated diene group. A cyclene with two typically hybridized sp carbons would require colinearity of four atoms and a 1,2-cyclodiene with one sp-hybridized carbon would have three carbons colinear. This restriction has limited the isolation of cyclynes to an &membered ring and of 1,2-cyclodienes to a 9-membered ring. However, experiments have shown that intermediates containing these groups in 5 to '?-membered rings can be formed in solution and trapped to yield addition products (@). Another facet of bond angle strain which has drawn special attention is bridgehead reactivity and rings which defy Bredt's rule. Bredt's rule is an empirical formulation applied to bridged-ring systems to define the minimum geometrical requirements necessary to accommodate a double bond at a bridgehead position. A rule-of-thumb description of Bredt's mle has been that if the sum of the number of atoms in the bridges of a bicyclic system is designated S, then compounds with bridgehead double bonds should be isolable only if S 2 9, and reactions of compounds via transient intermediates with bridgehead double bonds will occur only if S 2 7. This formulation has been a challenge to chemists to synthesize compounds which defy Bredt's rule and for ycars the smallest ring in compounds isolated with a bridgehead double bond was S = 9. Recently, the compound XI1 (S = 7) was prepared independently in two laboratories (43, 44). It was reasoned that the stability of a bridgehead double bond should be related to the stability of a trans cyclene. Since trans-cyclooctene is known (the smallest trans cyclene isolated), it was anticipated that XI1 should be isolable (41).
Bridgehead reactivity depends upon the cationic, anionic, or radical character of the bridgehead transition state. Broadly speaking, for compounds with S _< 7, reactions via carbonium ions are very slow, reactions via a carbanion may be speeded up, and those via free radicals occur with the same facility as in acyclic systems. For example, nucleophilic replacement of halogen or the deamination of amines a t norbornane bridgehead positions are unsuccessful. Bridgehead reactivities via carbonium ions vary over 13 powers of ten. One of the best quantitative analyses of ring strain and its correlation with reactivity was a study of a group of polycyclic bridgehead bromides XIII-XVII (46). Their rates of solvolysis can be related to the increase in angle strain during ionizaVolume 47, Number
I , January 1970
/
51
tion, although other types of strain cannot be ignored. k,.1(80%Et OH)
k&O%Et
OH)
xv The reactivity of bridgehead radicals has also been studied in an effort to understand the most favorable geometry of aliphatic free radicals. Interpretation of early data does not clearly distinguish a rapidly inverting pyramid from a planar but easily deformed structure. Even so, conclusions must be drawn c a r e fully because of the difficulty in assessing the contributions made from inductive and field effects, bond angle strain, and delocalization (classical and nonclassical). After corrections are approximated for inductive effects, the following relative stabilities are derived (46) 1-butyl 10 1-adamctntyl 0 . 4
1-bicyclo[2.2.2loctyI 1-norbornyl lo-a
Thus, the almost planar 1-adamantyl radical behaves virtually as an ordinary tertiary radical with a slight geometrical destabilization.
As predicted by the Woodward-Hoffman orbital symmetry rules, thermal sigmatropic rearrangements of small rings require relatively vigorous conditions and proceed generally via multistep processes involving diradical intermediates. As a generality, greater ring strain facilitates rearrangement. For illustration, the thermolytic activation energies of some bicyclanes decrease in the order bicyclo[3.l.O]hexane (57-61 kcal/mole), bicyclo[2.l.O]pentane (47-52 kcal/mole), and bicyclobutane (-41 kcal/mole). Space permits no more than a few examples of the thermolytic behavior of strained rings (48). Cyclobutane rings undergo 0 cleavage during pyrolysis
Vinylcyclobutanes undergo ring expansion
1,s-H shifts
Bicyclopentanes (and bicyclobutanes) have attracted considerable attention, mostly to their unusual reactivity of the zero-bridge bond. For example, bicyclopentanes readily undergo thermolytic isomerization
Ring Strain and Thermolytic Rearrangements
As a means of learning more about the chemical consequences of ring strain, considerable attention has been given to the thermal rearrangements of alicycles. The general objective has been to describe the energy surfaces on which these hydrocarbons exist and the mechanistic pathways by which they are interconvertible, including some knowledge about the intervening states or intermediates and the relevant activation energies. Several types of thermally induced isomerizations have been of interest. including valence tautomerism. typified by bullvalene, and sigmatropic rearrangements, such as the Cope rearrangement and 1,3- and 1,5hydrogen transfers. Ring strain may affect the rates of these latter rearrangements, however, they take place via transition states largely stabilized by T electron delocalization. There are some rearrange ments which are primarily driven by relief of ring strain, although even these may also be influenced a little by a or a electron delocalization. I n some cases, these skeletal changes have important theoretical implications or synthetic value. For example, the easily obtainable vinylcyclopropanes are isomedzed to 1-substituted-3-cyclopentanes(47).
52
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Journal of Chemical Education
The activation energies for these rearrangements are lowered through resonance stabilization of the diradical intermediates. For instance, ry vinyl groups lower the isomerization activation energies of cyclo-propanes and -butanes about 14 kcal/mole per vinyl group. Summary
I n summary, highly strained rings show a propensity for the following properties commensurate with the degree of internal stresses present Large heats of combustion and hydrogenation. Unsaturated character of carbon-carbon single bonds, shown by (1) addition reactions. (2) olefinic character of the C-H bonds, as reflected by acidity of H, stability of C ; resistance to H abstraction, and large J ( W - H ) coupling constants. Generally, high rates of solvolysis. Generally, relatively facile themolytic rearrangements.
Literature Cited (1) FEnaosoN, L. N.,J. C n w . Eouc., 46, 404(1969). (2) BROWN, H.C..FLETCXER. R. S..*ND JOXANNESSEN. J . Am. Chem. Soe.. 73,212 (1951). (3) Bnowx, H. C . , A N D IBHIRAYA, K.,Tetiohrdron 1, 221 (1957); H e c ~ , R., hlin P n e ~ o aV., . Helu. C h h . A d o . 38, 1541 (1955). (4) BROWN,H. C . , A N D D A R I O W S K I . M.,J . Am. Chem. Soc.. 74, 1894 (10'2>. ,...-,. (5) GARRETT, R.. A N D BOBLER. D. G.. J . O W. Chem., 31, 2666 (1866): Pnmoa, V.. A N D KOBELT,M.,Helu.'Chim. ~ c t 32, a 1187 (1949). e , D..Ow Rsachona, 8,364 (1954). (6) G u ~ s c ~C. (7) DAUHEN, W. 0.. CHITTYOOD, J. L.. A N D SCIIERER, K. V. JR., J . Am. Cham. Soc., PO, 1014 (1968).
