Philip J. Chenier University of Wisconsin-Eau Claire Eau Claire. Wisconsin 54701
The Favorskii Rearrangement in Bridged Polycyclic Compounds
This can be classified as an intramolecular rearrangement from carbon to carbon, involving a migrating group Zmoving without its electrons from migrating origin A to an electron-rich terminus B. The Favorskii rearrangement has been the subject of intensive research by many organic chemists since its discovery in 1894 (1). But despite its age, thereaction remains novel. Its mechanism and stereocbemistrv are currentlv beina studied. It is becoming an increasingly reliable instrument of organic svnthesis. A number of earlier summaries on the Favorskii ;arrangement are available ( 2 4 ) . The purpose of this article of is t o review the more current literature on the aoplication .. this rearrangement to bridged polycyclic compounds whvre it has been used in the synthesisand study of strained molecules.
is reached and how experimental conditions and structural variation in the halo ketone affect its formation. For instance, in the reaction of Ar-CH-CO-CHXR with sodium methoxide/methanol, there is much evidence for the following detailed mechanism, first proposed by Dewar 0
Mechanism
The general reaction involves the base-catalyzed rearrangement of an a-halo ketone to a carboxylic acid, an ester, or an amide depending on the base used. I t can be classified as an intramolecular rearrangement from carbon to carbon involving a migrating group Z moving without its electrons from migration origin A to an electron-rich terminus B. This type of rearrangement is sometimes called an electrophilic or ionic rearrangement.
No fewer than fivemechanisms have been advanced for the Favorskii rearrangement at one time or another. The mechanism of the reaction apparently is determined by the presence of absence of a hydrogen on the a' carbon atom. Two mechanisms seem to have stood the test of time and experimentation. The cyclopropanone mechanism of Loftfield (7) is the preferred pathway when an a'hydrogen is present. His brilliant work with Cl*-labelled 2-chlorocyclohexanone established the necessity of a symmetrical intermediate (such as a cyclopropanone) formed in the reaction pathway at some point. Recent work by Bordwell(8) and others (9) has centered on the exact way in which the symmetrical intermediate 286 / Journal of Chemical Education
CH,OH
Ar-CH-CHR
Ar-CH2-CHR-CO&H:,
(111) The reversibilitv of the first steD (k-1 >> k 9 ) is demonstrated for R = H hy deuterium exchangcstudi&and a large hnrlk"effect. Ionization of the halogen from the enolate inn (I) form the dipolar ion (11) is indicated by a large negative o. a sizable oositive salt effect, and a strona rate acceleration when the iinizing power of the sul\,ent is increased. When R = CHq then k? >> k-, and the first itep no longer is revenihle, as is eiidenced by the absence of deuterium exchange and any difference in rate of the bromide and chloride. A variety of ?vidence from other studies (8) suggests that the dipolar ion (11) is in equilibrium with the corresponding cyclopropanone (III), which eventually further reacts via the Loftfield mechanism to give product. The second a c c e ~ t e dmechanism for the Favorskii rearrangement is found in halo ketoncs which have no c,'hydwgm. This reaction has been called the abnormal or suns:-Favorskii rearrangement. The Bordwell-Loftfield mechanism cannot ooerate here. and vet Favorskii products have been isolated frarm many such reactions. This secund mrchanism has heen called thesemihenzilic mechanism in view of itssimilarirv r o the benzilic acid rearrangement (10). I t was first proposed by Tschonbar and Sacknr in 1939 (11,12). This mechanism involves addition of alkoxide to the carhonyl carbon of the halo ketone, followed by a concerted displacement of halide ion by the 1,2 migration of an alkyl group with its electron pair.
Much evidence against this mechanism exists for those cases of halo ketones with a' hydrogens. Nonetheless, it seems to be the best alternative for rearrangements such as the one below CI
0 0 At least one study has been done on a halo ketone that apparently reacts via the semibenzilic acid mechanism instead of the cyclopropanone pathway even though an a' hydrogen is present (13). When 2-hromocyclobutanone is treated with D20, deuterium is incorporated only into the acidic hydrogen but not in the ring. This would he predicted by the semihenzilic but not the cyclopropanone mechanism.
on
OD I
Undoubtedly the highly strained bicyclic cyclopropanone shown above makes the second oathwav much less favorable. Neither would the enolate ion'in this-small ring system be oarticularlv stable. The choice of hase and solvent can profoundly affect the yield of Favorskii products, but no single base-solvent combination appears to be clearly superior for all halo ketones. Sodium hydroxide and alkoxides are farorire bases; ethcrs, alcohols, and water are good solvents. Sodium hydroxide in an inert solvent appears to be the reagent of choice in quasiFavorskii rearrangements (11,12). Monocycllc Favorskll Rearrangements The ring contraction of a-halo cyclanones to carboxylic acid derivatives of the next lower ring size is an important synthetic application of the Favorskii reaction. Under appropriate conditions, yields of 40-75% can be obtained for cyclic u-halo ketones from six to ten carhons. 2-Rromncyclododecanone and its 2-chlom analor! also ha\.e been reported to undergo the rearrangement (14-16)
Of particular relevance to the present study are the smaller rine sizes of four and five carbons. Two unsuccessful attemots to rearrange 2-chlorocyclopentanone have been reported (1 7, 18). u
~~~
rearrangement of 2-bromocyclobutanone via the semiben7ilic mechanism. In summary, the six- and highcr-membered rings rearrange by way of a eyclopropanoue,~thefour-membered ring prefers a semibenzilicmechanism, and the five-membered ring undergoes a different reaction entirely. Blcyclo [3.3.1] Rearrangements In contrast to acyclic and monocvclic studies of the title rearrangement, theiiterature on bridged compounds is more recent and contains fewer examples. The tahle lists all known examples of successful rearrangements of this type found in the literature through 1976, and includes compounds (1V)(XXI) and references (19)-(38). The first example of a Favorskii rearrangement in this type of system was reported by Cope (19,20) in 1950.1-Bromohicyclo[3.3.l]nonan-9-one (IV) was shown to rearrange under a varietv of conditions to bicvclol3.3.0loctane-l-carboxvlic acid or & derivatives. This wa5 thh first example of a bridied bicvclic halo ketone which underwent rina- contracrion bv t his type of reaction. Cope interpreted this result in terms of a "push-pull" mechanism which is the semibenzilic pathway discussed earlier. The formation of an intermediate cyclopropanone was thought to be unlikely here, since the hydrogen is at a hridgehead position. Loss of a proton at C-5 would form a carhanion which could not he stabilized by r overlap with the carhonyl, since the enolate ion would violate Bredt's rule.
(rV) unstable A later example (21) of this same size bicyclic ring rearranging twice in the same compound is the reaction of diketone (V). Here both halides are a t bridgeheads, both ketones are on one-carbon bridges, and there are two bicyclo [3.3.1] cages. Polycycllc [2.2.1] Rearrangements This very novel reaction of otherwise inert hridgehead halides remained unexplored until the synthesis of the cuhane system, including a step in which dihromo diketone (VI) rearranges to a cuhane diacid (22.23). As in Cope's reaction, the bromines are a t the hridgehead positions and the carhonyls are on the single carbon arms of the bridged structure. Both a' carbons have a hydrogen and these also are bridgehead positions. Eaton and Cole therefore reviewed the reaction as being semibenzilic in nature. What was novel about their work was that they proved that this unusual reaction could be performed on what amounts to a bicyclo[2.2.1] system, even more strained than usual because of the caged nature of the structure. The svnthesis of the oarent hvdrocarhon cubane bv the same workers ( 2 4 )involves two Favorskii reactions of similar natureon brorno ketones (V11Jand (VIII). 1)ibn)modiketone (IX) also rearranges to a cuhane derivative analogously (25). Chloro ketones (X) and (XI) rearrange cleanly even though they contain no a' hydrogen, necessitating the semibenzilic mechanism (26). However, the similar chloro ketone (XXII) undergoes ring opening in a type of Haller-Bauer cleavage (39) to give a chlorinated acid. COOH
'%omplete resinification" Mention has already been made of the successful Favorskii Volume 55, Number 5, May 1978 / 287
Successful Bridged Polywclic FavorPii Rearrangements Refer-
Bare-solvent
Reactant
d3
Rearranged Product
ence
m
KOH, ethel
COOH
HgIOAcl,.
EtOH
COOH tester
m
Na or NaNH, iiq. NH,
CONH,
(N)
bBr
4
alc K O H
COOH
0
. .
BF
hH 4.
50% sq K O H or 25% NaOH
OCH,
i?l;'
0
10%-
KOH
OCH,
IW)
&lr
25% aq K O H
n
= 6.7.8 carbons in ring
KOH. xylene or 10% sq K O H
288 1 Journal of Chemical Education
ReferBare-solvent
Rearranged Product
ence
This ring breaking is apparently a serious side reaction, since (XXIII) reacts similarly but with subsequent loss of HC1 to form a double bond (26).
8'
NaOH. toluene
-
C17 aq. KO"
c1 3U%
aq K O H
HOjlq$a? --pjC
NaOH. benzene
+
+
C1
Cl F,
-
COOH
COOH
HOOC
NaOH. T H F
COOH NaOH. T H F
COOH
NaOH, T H F
89%
NsOH, 95% aq T H F
64%
Other examples of successful Favorskii rearrangements in polycyclic[2.2.1]-containingsystems are shown in the table for compounds (XII), (XIII), and (XIV). However, chloro ketone (XIV) with sodium hydroxide in benzene forms the ring-cleaved acid as the major product, although the Favorskii product is also formed. With potassium hydroxide, no Favorskii product is formed (29).
C1 COOH H major
0 (XIV) dil. aq K O H 1 5 ~ ~ C
c1
varied
COOH
CI
NsOCH,/CH,OH or glyme
major only NaOCH,/CH,OH or glyme
Bicyclo [2.2.1] Rearrangements
The parent bicyclic compound of the above polycyclic structures is bicyclo [2.2.1] heptan-7-one. The simple dichloro ketone (XV) and derivatives with substituents a t C-2 such as (XVI) and (XVII) undergo ring contraction (3@33). McVolume 55. Number 5, May 1978 / 289
Donald and Curi (33) deduced that a stepwise, nonconcerted semibenzilic rearrangement must be taking place, where a carbanion as a discrete intermediate is formed only on the carbon nearer to the stabilizing, electron-withdrawing methoxy group of (XVII).
0CH3
A semihenzilic mechanism is postulated, although intermediate (XXV) would not be ideal because of a steric effect of the 7-methyl.
(XXV) Nevertheless, the synthetic usefulness of this rearrangement for making bridgehead-substituted bicyclo[2.l.l]hexanes is demonstrated. Application of the rearrangement to more highly strained systems has failed thus far. 1-Chlorobicyclo[2.1.l]hexan-%one (XXVI) gives only ring opening with aqueous hydroxide
OCH,
(40).
If the reaction were concerted, elimination of the other chlorine would be just as favorable and the isomeric product (XXIV) would be formed.
hH OCH,
(XXIV) The menacing ring opening occurs with (XVI) and (XVII). McDonald and Curi found that this was a function of solvent. As the solvent became more protic, larger amounts of ring opening occurred via cwbanion capture. This seems to explain the previous cases of ring opening also, where presumably similar structures give various percentages rearrangement versus ring fracture. When a proton donor is available in a quasi-Favorskii reaction, the carbanion is captured before it can attack the a halo substituent.
o=L
