Rlchard W. Holder University of New Mexico Albuquerque, 87131
Ketene Cycloadditions
Ketenes are reagents of the general structure
R'
I
R-C=C=O and are one of the more interesting and useful members of the small class of heterocumulenes. The most common methods of preparing ketenes include
n
R'
the two suhstituents are joined in a ring provide convenient approaches to interesting spirocyclic compounds (24,25). Beyond the synthetic importance of the cycloaddition reactions of ketenes, these processes recently have received considerable attention as to the mechanism(s) traversed. It is the purpose of this paper to survey the more recent experiments reported on the thermally activated cycloadditions of ketenes and alkenes, and to analyze the current mechanistic proposals in the light of the available stereochemical and energetic parameters. Stereochemical Variables: Some Definitions If more than one pericyclic reaction (26-32) is possible for a ketene then the stereochemical variable of perispecificity must be studied; i.e., which process is selected by the ketene and what is the quantitative preference for that process. For example, a ketene is allowed by the considerations of orbital symmetry (26) to cycloadd to 1,3-cyclopentadiene (acting as the ketenophile) in either a ( r 2 r4) or a (x2 r 2 ) manner. In the event, with cyclopentadiene and
.+
+
dehydrohalogenation of an acyl halide (I-3), dehalogenation' of an a-haloacyl halide (4-7), and pyrolysis of an anhydride (8)or ketene dimer (9). Ketene itself (CHFC=O) is made by the pyrolysis of acetone (9). Much of the early work on ketenes was done by Staudinger, and was reviewed by him (10). Later reviews on cycloadditions (9, 11-13) have included discussions of ketene chemistry. As strong electrophiles ketenes react with alcohols (or amines) to form esters (or amides)
R'
I
R-C=C=O
+ R"OH
+
RR'CHCOOR"
with diazoalkanes to form cyclopropanones (I4), and with each other to yield 1,3-cyclobutanediones or &lactones (15)
and with alkenes or alkynes in an analogous cycloaddition reaction to form cyclobutanones (10) or cyclohutenones (16, 17). The latter (2 2)
+
cycloaddition constitutes one of the few routes (18) to synthetically versatile (19-21) four-membered rings. It has been utilized for a high-yield preparation of tropolone ( I ) and as a key step in the total synthesis of several important prostaglandins (22, 23). Reactions of haloketenes with methylenecycloalkanes or utilization of ketenes in which
+
other non-hetero 1,3-dienes the (2 2) cycloaddition mode is the exclusive choice (33-35) of all reactions ~ t u d i e d . ~ The evident reluctance of ketenes to participate in ( r 2 + r 4 ) pericyclic reactions is confirmed by the high temperatures required for retro-Diels-Alder reaction of even a potentially aromatic system (38,39). We must
conclude, therefore, that ketenes react with alkenes with high (2 + 2) perispecificitv. i f we coniinue'to utilize l,3-cyclopentadiene as a model suhstituted alkene it is plain that there are three additional stereochemical featured of interest: the geometry of the newly formed ring fusion; the regiospecificity of the reaction with respect to the location of the remaining double bond; and the orientation of the addition with reference to the positions the ketene suhstituents assume in the adduct.
' It has been suggested that free ketenes are not generated by this procedure; instead a zinc-ketene complex (a ketenoid) may be formed (7). .. Diels-Alder adduets have been observed in systems containing heteroatoms, such as a,P-unsaturatedketones (12,36,37). Volume 53.Number 2 February 1976
/ 81
Regiospeciticity
andlor R'
0+
I
R-C=C=O
+
R'
Geometry
The geometry of ketene addition to a double bond normally involves suprafacial comhination for the alkene so that complete retention of configuration for the doublebond suhstituents is observed. This seems to be the case especially for cis-alkenes with which the cycloadditions are more facile than with the trans-isomers. Early degradative work (40) showed that ketene itself adds to cyclopenta-
C)+
H&=C=O
+
9 qCmH 5
0
COOH
+
diene to form the cis-fused product. Thermal (2 2) cycloreversions of cis- and trans-2,3-dimethylcyclobutanone(41, 42) provide 2-butenes with more than 98% retention of stereochemical intearitv.
The principle of microscopic reversibility then requires the (2 + 2) cycloaddition of ketene to the 2-butenes to be suprafacial with similarly high stereospecificity. As the bulkiness of the ketene and alkene suhstituents increases, however, the reactions sometimes lose this suprafacial alkene stereospecificity. When dimethylketene cycloadds to the 2-butenes (43, 44) the reaction is quite stereospecific for the cis alkene but much less so for the trans isomer, which also is less reactive.3
+ >C=C=O
+
(no trans)
Cycloadditions of ketenes to allenes also have been ohserved to proceed with a loss of stereochemical control about the reacting double bond (46-52). In one definitive example (46) tert-hutylcyanoketene was allowed to react with enriched S-(+I-2,3-pentadiene. Isolation of four isomeric cyclohutanones, two optically active and two optically inactive, indicates extensive loss of the "normal" alkene suprafaciality. Since eyelohiitanones are labile to (adventitious) base catalyzed epimerization ( 4 5 ) appropriate control experiments are necessary before conclusions are drawn regarding this stereochemical variable. 82
Journal of Chemical Education
Although early workers took precautions to prove the regiospecificity of ketene-alkene cycloadditions by product degradation or independent synthesis (53, 54) and some later investigations have used similar techniques (55-571, atregiaspecificity tention to this aspect of the stereochemistry has been sporadic. In some cases regiospecificity has been assigned on the hasis of an assumed mechanism (I) or from nmr studies (58, 591, although this latter techniaue used alone can he unreliable (60). If we consider the intermediates (zwitterions or diradicals) which could result from stepwisk addition of ketene to cyclopentadiene (I-IV), it is obvious that only I1 can be stabilized by the interaction of both valence deficient centers with
neighboring unsaturation. In fact, the only product ohserved (40) is that which would come from closure of this intermediate. This consideration does not establish a stepwise mechanism, however, since postulation of a transition state involving charge separation so that the alkene acts as a nucleophile leads to the same expected regiospecificity
In fact, there is good evidence for charge separation somewhere along the reaction coordinate. A linear Hammett plot was observed for the cycloadditions of diphenylketene to 1,l'-diarylethylenes and styrenes (61); a modest rate enhancement in more polar solvents was noted for the additions of diphenylketene to n-butoxyethylene (34); and a small isotope effect was measured for the reaction between diphenylketene and 1-deuteriocyclohexene (62). These results are supported by recent measurements of the energetic parameters for gas-phase cycloreversions of suhstituted cyclobutanones (63). In fact, for all cases in which secure structural assignments have been made the regiospecificity always is in agreement with the prediction based either on a chargeseparated transition state or a zwitterionic intermediate. For example, dichloroketene adds to cyclopentadiene with the expected regiospecificity (64). The enhanced electrophilicity of this ketene was shown not to affect the regiospecificity, since dechlorination of the adduct (65) provided the same species obtained previously from the reaction of ketene itself and cyclopentadiene (40).
Orientation
Several elegant studies (58, 59, 66) show conclusively that unsymmetric ketenes add to cyclic~alkenesso that the bulkier substituent assumes the more crowded endo position in the adduct. The product ratios shown in Table 1 illustrate the generality of the effect. There is no doubt in these cases that the structural assignments are correct, since both endo-H and endo-CHa absorb in the umr a t considerably higher fields than the corresponding exo suhstituents. Thus, the adduct of cyclopentadiene and dimethylketene (67) shows two methyl singlets in the nmr; one a t 60.93 and the other a t 61.23
(69).Reduction of the adduct produced a single alcohol; a complete structural analysis of the crystalline p-bromobenzoate derivative by x-ray spectroscopy confirmed all the conclusions derived above.
9
CIOkc/O I
A Nuclear Overhauser Effect can be observed (58) between the downfield methyl signal and the vicinal bridgehead hydrogen at C1. Steric considerations indicate that kinetically controlled methylation of the cyclopentadiene-ketene adduct should give predominately the exo-7-methyl product; the principal isomer actually formed has a methyl doublet absorption at 61.23. This species is epimerized under basic conditions to the isomer whose methyl absorption falls a t 60.96 (66). This latter compound, in turn, is identical to the major epimer available from the cycloaddition of methylketene to cyclopentadiene (461, which therefore has the endo-7-methyl configuration.
Ketene Readivily
Ketenes ordinarily are so reactive that they are prepared and used in situ; even diphenylketene, atypical in that it can he isolated and stored for long periods, cycloadds to nbutoxyethylene (34, 70) with the low activation enthalpy LW~ = 9.3 kcallmole (ASS = -40 eu.). The electrophilic character of ketenes is reflected further in the reactivities shown by different ketenophiles. Apparently the reaction rates depend extensively on the electron density at the double bond of the alkene (70). Table 2 presents data which show not only this electronic effect, but a smaller, superimposed steric effect of decreasing rates with increasing hindrance to approach of the ketene. Mechanistic Considerations
Woodward and Hoffman (26) have analyzed ketene-alkene cycloadditions in terms of a (s2s a2a) concerted reaction in which the ketene plays the antarafacial role. I t is ideally constituted to behave in this manner because secondary bonding interactions between the olefinic p-orbitals and the low-lying s*,, orbital of the ketene molecules are possible. This type of interaction is maximized for the ketene and alkene in a perpendicular confrontation; Figure 1 shows this mode of approach for a ketene and a diene, in which (for simplicity) the a*,=, orbital is replaced by an
+
As will he discussed later, this substituent orientation is explained best by an orthogonal approach of ketene to alkene; such orthogonality also accounts for the observed stereochemistry of the cycloadditions of dichloroketene to 2-cholestene and 4-tert-butylcyclohexene (6,681. Summary of Stereochemical Parameters
In summary to this point it is clear that ketenes ordinarily cycloadd to substituted alkenes with (s2 a2) perispecificity, suprafacially with respect to the alkene, with a regiospecificity explicable by assuming charge separation somewhere along the reaction coordinate, and with an orientation for the ketene substituents which places the larger group in the more hindered (endo) position in the product. These generalizations have been confirmed rigorously for the reaction between chloroketene and cyclopentadiene
+
Table 1.
Table 2.
Relative Rate Constants in Benzonitrile at 40DC 170) IC.H,i,C=C=O
Alkene a = b C6HsCH=CH, C,H.OCH=CH,
+
a=h
A
C,H,
C,H,
Relative Rate 1.O 196
Orientation of Ketene Subrtituents in I2 + 21 Cycloadditionr (581
Volume 53. Number 2,February 1976
/ 83
s 1'
------ P
Figure 1. Concerted and stepwise
doadjiiion.
int.rartion tnt...rllon
s
i
L
= l..~.
sm.11
%ubstilu.nt sub.llfu.nl
+ 2 ) cycloaddiiion:
L = Large Sub-
mechanisms far (2 + 2 ) ketenediene cy-
unoccupied p-orbital of the ketene in its vinylium ylide resonance form4 (72).
I t should he noted that the sterically favored approach nlaces the lareer ketene suhstituent awav from the diene i ~ i 2). ~ The . subsequent concerted then involves honding of C2 to Cg and of C1 to C4, a skewing motion t o align bonds 3-4 and 1-2, and a 180" rotation uncoupling hond 1-2 to present the honding lobe of C1 to that of Cq. Even if these complex motions are viewed as concerted it is reasonable to suppose them to he non-synchronous, i.e., formation of hond 2-3 leads that of hond 1-4 so that charge separation exists in the transition state. This charge distribution (negative on the ketene and positive on the ketenophile), together with the motions and bond reorganizations described, provide a 3-vinylcyclohutanone with the geometry, regiospecificity, and substituent orientation ordinarily observed. Recently new theoretical models using perturhation theory or configuration interaction calculations (73, 78) have been developed which attempt to rationalize perispecificity, regiospecificity, suhstituent effects, solvent dependencies, and other variables involved in concerted processes. Unfortunately this work has shed little additional light on ketene cycloadditions. Even with the predictive advantages of the orhital symmetry approach (26), or the equivalent procedure involving aromatic transition states (27, 28, 32) it is pertinent t o recognize the "rules" as permissive only. Reactions are free to choose a non-concerted pathway involving diradicals (79) or zwitterions; under some conditions they even may undergo a "forbidden" reaction in a concerted manner (80,81). For ketene-alkene cycloadditions a two-step mechanism (also shown in Fig. 1) also can explain the known data. In
' "'C-YMR
of kame has * h o w this rnesurnerw structure to hc less important than Hf" -Cm-O 171J.
84 /
Figure 2. Orientation in ketenediene (2 stituent. s = Small substituent.
Journal of Chemical Education
this case what might he termed "orhital approach control" mandates the same orthogonal approach of the reactants as in the concerted mechanism, hut hond 2-3 is formed first to give zwitterionic intermediate A. This species then must pivot 90" about hond 2-3 as hond 1-2 undergoes a 180' rotation (shown as two 90' steps) to form species B, which closes to the observed nroduct. If the p-orbital exeking the orhital approach control in this model is attacked directlv. hv - the end of the nucleophilic diene (82) species A of Figure 1is generated directly. This picture is more economical of motion and, when the basis-set orbitals of oxygen are included, it rationalizes the preferred ring closure to cyclobutanones (rather than oxetanes). The large range of reactivities dictated hy hoth electronic and steric effects, and the occasional loss of suprafacialitv about the ketenophilic double hond, is compatible with the existence of a mechanistic continuum for the ketenealkene cycloadditions. At one end of the scale the reactions are concerted (r2a r2s) processes with non-synchronous hond formation. At the other end of the continuum thereactions occur by two discrete steps, separated by a zwitterionic intermediate. In the concerted reaction the governing effect of orhital approach control is the interaction between the highest occupied molecular orhital (HOMO) of the alkene and the lowest unoccupied molecular orhital (LUMO) of the ketene. As electron donating suhstituents are attached to the ketenophile, the HOMO of this partner is raised, thus facilitating the HOMO-LUMO interaction and increasing the reaction rate. These cases, however, show greater charge separation as measured by their sensitivity to solvent polarity (70). When the charge separation reaches zwitterionic proportims the mechanism hecomes stepwise. SCF perturhation calculations (78) ha\.e shown (77) that, after the preferred orthogonal approach, in many cases near the middle of this mechanistic continuum the concerted and non-concerted mechanisms are balanced closely. In extremes satisfactorilv acanv event. - ~hoth ~ mechanistic ~ , count for the geometry, regiospecificity, suhstituent orientation. and laree neeative e n t r o ~ i e sof activation cited (26) in support of concert alone. Even modest solvent depen-
+
~
~~~
~
~
- -
