Reactive Intermediate Chemistry

Scheme 7.3

attack on the carbonyl group of cyclobutanone. A zwitterionic intermediate, 10, leads to the ring-expanded, masked diketone (11, Scheme 7.4). When either of two substrate carbons can be involved in the expansion, selectivity favors migration of the more substituted carbon.

Scheme 7.4

Similarly, Rigby and coworkers51 used the oxadiazoline method to generate dithiacarbenes, which initiate nucleophilic attacks on isocyanates (Scheme 7.5). In this case, nucleophilic attack on the isocyanate ‘‘carbonyl’’ leads to ring closure via intermediate 12. The proximate product then undergoes an apparent N H insertion reaction with a second carbene to yield the final product. The philicity of the N H insertion is unclear; it could be initiated by ‘‘electrophilic’’ attack of the ambiphilic (C3H7S)2C on the substrates’s nitrogen lone pair, or it might originate in N H proton abstraction by a ‘‘nucleophilic’’ carbene acting as a base. Related reactions of (CH3O)2C with isocyanates are known.52

CH(SC3H7 )2

Scheme 7.5

Finally, addition reactions of the isolable phosphasilylcarbenes (13) to such electron-poor substrates as methyl acrylate, C4F9CH CH2, and styrene afford cyclopropanes. The additions of 13a to (E)- or (Z)-b-deuteriostyrene are stereospecific, and the competitive additions of 13b to ring-substituted styrenes exhibit nucleophilic selectivity, consistent with singlet, nucleophilic carbene addition (Fig. 7.8).53

..

(R2N)2P–C–Si(CH3)3

13a, R = i-C3H7; b, R = cyclohexyl

Figure 7.8

2.1.2. Rates and Activation Parameters. The first condensed-phase absolute rate measurement for a carbene–alkene addition was reported by Closs and Rabinow in 1976: flash lamp photolysis of diphenyldiazomethane generated

are faster, and their addition reactions are too rapid for the time resolution afforded by a flash lamp.

The development of laser flash photolysis (LFP), with flash times of 10–20 ns, made possible the measurement of many absolute rate constants for singlet carbene additions. The initial reports focused on chlorophenylcarbene (C6H5CCl)55 and singlet and triplet fluorenylidene.56 Consider C6H5CCl: LFP at 351 nm of chlorophenyldiazirine (14) in isooctane containing a given concentration of an alkene such as (CH3)2C C(CH3)2, affords a transient ultraviolet (UV) signal for C6H5CCl at 310 nm that decays as the carbene adds to the alkene. In the absence of an alkene, the carbene can decay by dimerization, by reaction with the diazirine precursor, or by reaction with adventitious water. When sufficient alkene trap is present, however, these pathways are suppressed. From the time dependence of the carbene signal’s decay, we obtain a pseudo-first order rate constant (kobs) for carbene–alkene addition. Variation of the alkene concentration and repetition of the LFP experiment yields additional values of kobs, and correlation of kobs with [alkene] gives a straight line, the slope of which is the second-order rate

Scheme 7.6

288 SINGLET CARBENES

Moreover, we see that the nucleophilic properties of CH3COCH3 are pronounced (Tables 7.3 and 7.4): the combination of a relatively high-lying, filled HOMO donor orbital ( 9.4 eV)33 and a high-lying, poorly accessible vacant p orbital (LUMO, 4.0 eV)33 makes CH3COCH3 a good nucleophile and a poor electrophile. The computed differential orbital energies for additions of CH3COCH3 to the alkenes of Table 7.4 are dominated by the nucleophilic eN term.

The CH3O for CH3 substituent swap that transforms CH3COCH3 into (CH3O)2C results in additional stabilization of the carbene and lower reactivity. Thus, (CH3O)2C, with eLU ¼ 4:3 eV,40 no longer adds to electron-rich alkenes such as (CH3)2C CHCH3, dimerizing instead, whereas its nucleophilic additions to

electron-poor olefins, such as CH2 CClCN and CH2 CHCN, are 100–1000 times slower than those of CH3COCH3.33,40

If the resonance stabilization of singlet carbenes is increased even more, for example, by replacing the CH3O substituents of (CH3O)2C by amino groups [as in (R2N)2C] or phosphorus substituents (13), stable, isolable, nucleophilic carbenes can be obtained. These species are considered in Chapter 8 in this volume.

Given our ability to measure absolute rate constants for carbene additions, variable temperature studies readily afford activation parameters.57,63 Initial studies of C6H5CX additions gave very low Ea values, 1 kcal/mol for reactions with 1-hexene and trans-pentene.66 Most surprisingly, the Ea values for C6H5CCl additions to (CH3)2C C(CH3)2 and (CH3)2C CHCH3 were negative ( 1.7 and 0.8 kcal/ mol, respectively). The reaction rates increased as temperature decreased. The preexponential (A) factors were low (2–6 107 M 1 s 1), indicative of an unfavorable entropy of activation.

The most convincing explanation for the negative activation energies was offered by Houk et al.,67 who computed H, S, and G for additions of CBr2, CCl2, and CF2 to (CH3)2C C(CH3)2 and (CH3)2C CH2. With CBr2, a very reactive carbene, and the highly reactive (CH3)2C CHCH3, the addition reaction was so exothermic that H continually decreased all along the reaction coordinate. Therefore, Hz and Ea were negative. However, the loss of the translational, vibrational, and rotational entropy required in the transition state for addition led to an unfavorable and dominant entropy of activation ð Sz < 0Þ which, in turn, created a free energy barrier to addition ð Gz > 0Þ. With the more stable and less reactive carbene, CF2, Ea, and Hz were positive, adding to the Gz barrier.67 The key role

of entropy in carbenic additions, highlighted by Houk, was earlier noted by Skell and Cholod,35b and by Giese.68

A wide-ranging experimental study of carbene–alkene addition activation parameters examined a series of substituted arylhalocarbenes (16) in reactions with (CH3)2C C(CH3)2 and 1-hexene (Fig. 7.9).69

YC X

16

Figure 7.9

‘‘Extreme’’ cases were reactions of the least stabilized, most reactive carbene (Y ¼ CF3, X ¼ Br) with the more reactive alkene (CH3)2C C(CH3)2, and the most

mol for the slower reaction, mainly because of entropic contributions; the Hz components were only 1.6 and þ2.5 kcal/mol, respectively.69 Despite the dominance of entropy in these reactive carbene addition reactions, a kind of ‘‘de facto enthalpic control’’ operates. The entropies of activation are all very similar, so that in any comparison of the reactivities of alkene pairs (i.e., krel), the rate constant ratios reflect differences in Hz, which ultimately appear in Gz. Thus, carbenic philicity, which is the pattern created by carbenic reactivity, behaves in accord with our qualitative ideas about structure–reactivity relations, as modulated by substituent effects in both the carbene and alkene partners of the addition reactions.24

Finally, volumes of activation were measured for the additions of C6H5CCl to (CH3)2C C(CH3)2 and trans-pentene in both methylcyclohexane and acetonitrile.70 The measured absolute rate constants increased with increasing pressure;Vz ranged from 10 to 18 cm3/mol and were independent of solvent. These results were consistent with an early, and not very polar transition state for the addition reaction.

2.1.3. Symmetry of the Transition State. The asymmetric, ‘‘non-least-

motion’’ transition state (6) for carbene–alkene cycloaddition has been discussed in qualitative1,71 and quantitative34,36,67,72 terms for many years. As shown in Fig. 7.6, the transition state features carbene p–alkene p* orbital interactions.24–26,36,42–46

Hoffmann first presented a theoretical analysis supporting a ‘‘p-approach’’ transition state (6), which also rationalizes the electrophilic character of CH2 or CCl2 addition reactions.34 He also showed that the symmetrical ‘‘least-motion’’ approach

(17) was forbidden by orbital symmetry.34 Subsequent computational studies supported Hoffmann’s conclusions.36,67,72 Note that although the trajectory of the addi-

tion reaction begins with the geometry represented by 6, the carbene must later pivot toward geometry 17 in order to complete the cyclopropanation (Fig. 7.10).

Keating et al.73 used natural abundance isotope effects to define the ‘‘direction’’ of the asymmetry for the addition of CCl2 to 1-pentene, and presented complementary

Figure 7.10

free carbenes, (C6H5)2C, C6H5CH, CCl2, and CH2, respectively. Carbenoids usually add electrophilically to alkenes. An extensive review of carbenoid philicity has recently been published by Boche and Lohrenz.77

2.1.4. Stepwise versus Concerted Addition. One of the factors that makes carbene chemistry fascinating is that regardless of which species is first formed, reactivity may issue from either the singlet or triplet state. In this chapter (and in Chapter 9 in this volume), we will have to consider the spin state of the reacting species in essentially all reactions. It is not enough to assume that the first-formed intermediate is the reacting species. Indeed, the singlet generally has an enormous advantage over the triplet. Nearly all molecules are ground-state singlets—all electrons are paired. Thus, they can be formed directly from singlets but not from triplets. Reactions of singlet carbenes are often exceptionally exothermic, and the formation of two new bonds in a single step from a singlet implies transition states that are very reactant-like (Hammond postulate), and thus with very low barriers. Nearly every time, when a singlet is close enough in energy to be formed from a triplet, it will be the intermediate that does the chemistry and forms the products. We will point out a few exceptions in this chapter, and be sure to see Chapter 9 in this volume as well.

As noted above, singlet reactions in general, and addition reactions in particular,

must benefit greatly from the exothermicity of the formation of two sigma bonds. That idea must have been behind the early assumption, made by both the Skell27,35c

and Doering groups,78 that the observation of a stereospecific addition would be diagnostic for the singlet state. Of course, that assumption not only posits that the addition of a singlet carbene would be one step, but that the necessarily stepwise addition of the triplet would not be stereospecific. In turn, those ideas assume that in the intermediate diradical formed in the first step of a triplet addition, rotation about a single bond would be faster than spin inversion (intersystem crossing—‘‘isc’’) and closure Scheme 7.8).

Scheme 7.8

292 SINGLET CARBENES

Surprisingly, the critical experiment has been done infrequently over the last one-half of a century! The requirements for an experiment that truly speaks to the issue at hand are that one be able to see the results of addition of both spin states of a single carbene, and these requirements rarely have been met. For example, the direct irradiation of methyl diazomalonate leads to the stereospecific addition expected of a singlet carbene, whereas the photosensitized decomposition of the diazo compound leads to formation of the triplet carbene and loss of the stereochemical relationship originally present in the reacting alkene. Rotational equilibration in the intermediate seems to be complete, as it makes no significant difference whether cis or trans alkene is used as starting material (Scheme 7.9).79

(CH3 OOC)2CN2

hν photosensitization

Scheme 7.9