Reactive Intermediate Chemistry

294 SINGLET CARBENES

Can one find counterexamples—addition reactions—or any reactions—in which singlets react in a stepwise fashion? In principle, the answer to this question must be yes—we need only find a reaction for which an intermediate, either diradical or dipolar, is strongly stabilized, whereas the transition state for the concerted reaction is destabilized. As the stepwise reaction becomes easier and the concerted reaction becomes more difficult, eventually the activation energy for the stepwise path will fall below that for the concerted reaction. How would one go about searching for such reactions? Brinker has suggested that the addition of dihalocarbenes to 1,2- diarylcyclopropenes83a (and 1,2-diarylcyclobutenes83b) involves a stepwise addition. The transition state for cyclopropanation is clearly destabilized by the strain inherent in the incipient bicyclo[1.1.0] system, and the halogens and aryl groups can stabilize a dipolar intermediate, as in 22. The reaction reveals itself not through stereochemistry, but by the formation of a ring-opened product 23 (Scheme 7.11).

Ar

22

Ar

Ar

CCl2

Ar

The relevant products are the dienes (23) which are the major products. The cyclobutenes are very likely formed from an intermediate bicyclo[1.1.0]butane. Three pathways leading to 23 are considered A, B, and C (Scheme 7.12).

Path C is surely unlikely for several reasons, chief among them is that 23 is formed even at 45 C, at which temperature the bicyclobutane would surely be stable. The real problem is to rule out the non-carbene mechanism, path A. Brinker cleverly does this by examining the dienes formed from 24 and 25 (Scheme 7.13). The products are nicely rationalized through intermediates 22a and 22b in which the direction of the initial addition is determined by the stabilizing or

CCl2

CCl2

Ar

Ar

23

Scheme 7.12

destabilizing effect of the substituent. Methoxy will stabilize an adjacent positive charge, but trifluoromethyl will destabilize it (Scheme 7.13). Were the reaction to take place through an anionic addition (Path A), the opposite results would be expected.

Does this experiment provide an airtight case for stepwise addition of dichlorocarbene? Not quite, as Brinker specifically recognizes in Ref. 83. The regioselectivity observed could come from polar transition states, and does not quite require an intermediate (Scheme 7.14). The case is strong, however.

Such a reaction, in which two bonds are broken in a single step, has precedent in the two-bond pluck mechanism proposed for the reactions of bicyclobutanes (and quadricyclanes) with carbenes (Scheme 7.15).84a In this reaction the transition state

298 SINGLET CARBENES

2.2. Carbon–Hydrogen Insertion Reactions

2.2.1. Intermolecular Insertions. Singlet carbenes undergo insertion reactions with X H bonds such as O H (alcohols), N H (amines), Si H (silanes), and so on. The reactions with alcohols can be extremely fast.86 Here, however, we focus on the C H insertion reactions of singlet carbenes,1 in which carbon–carbon bonds are created.87

In 1956, Doering et al. reported that methylene (CH2) inserted into the C H bonds of pentane, 2,3-dimethylbutane, and cyclohexene with no discrimination (other than statistical) between chemically different sites; CH2 was ‘‘classed as the most indiscriminate reagent known in organic chemistry.’’1,87 Doering88 and Kirmse89 also demonstrated that the C H insertion reactions of CH2 in solution were direct, single barrier concerted processes with transition states that could be represented as 27 (Fig. 7.12). In particular, they did not proceed via initial H abstraction to give radical pair intermediates that subsequently recombined. (Triplet carbene C H ‘‘insertions,’’ however, do follow abstraction–recombination, radical pair mechanisms, as demonstrated in classic experiments of Closs and Closs90 and Roth91 (see Chapter 9 in this volume).

Given the high reactivity and lack of selectivity of singlet CH2 toward C H bonds, let us focus on more stabilized and selective carbenes such as CCl2 and C6H5CCl. Insertions of singlet CCl2 can be efficient. For example, CCl2 generated by the phase-transfer-catalyzed reaction of NaOH and CHCl3 in benzene inserted into the bridgehead C H of adamantane in 91% yield (based on consumed adamantane).92 Similarly, CCl2 inserted into the indicated C H bond (bold) of ketals 28, in which R included a large variety of alkyl groups.93 Note that the reactive C H is both tertiary and activated by two a-oxygen atoms. With the related substrates (29) a Hammett study of CCl2 relative reactivities as a function of aryl substituents gave r ¼ 0:63 (vs. sþ), indicating that CCl2 insertion is electrophilic and imposes dþ on the substrate carbon, analogous to CCl2 addition to alkenes.94

A qualitative representation of the transition state for singlet carbene insertion might be rendered as 30, in which the appropriate partial charges are indicated. This formulation was offered by Seyferth et al.95 to account for their observations of selective CCl2 insertions into the tertiary C H bonds of various simple hydrocarbons,96 as well as the a-CH bonds of ethers. Indeed, in a Hammett study of CCl2

insertions into substituted cumenes 31 (with CCl2 generated by extrusion from C6H5HgCCl2Br at 80 C), Seyferth and Cheng97 found r ¼ 1:9 (vs. s) or

0.89 (vs. sþ), consistent with transition state 30 (Fig. 7.13).

Figure 7.13

Moreover, CCl2 insertion into the benzylic tertiary C H of (S)-2-butylbenzene (32) occurred with retention, as expected for direct C H insertion.97 Finally, the C D analogue of 32 gave kH=kD for CCl2 insertion as 2.5. This relatively small primary kinetic isotope effect, together with the low Hammett r value, suggest an ‘‘early’’ transition state, in which relatively little charge separation has developed.

Similar conclusions attend the insertions of CCl2 (from the thermolysis of Cl3CCOONa at 120 C) into a-deuteriocumene and cumene b-d6, in which the primary kH=kD ¼ 2:6,98 similar to Seyferth’s finding with 32, and the b-secondary kinetic isotope effect is 1.20–1.25 for six deuteriums.98 Here, hyperconjugation at the b-CH (CD) bonds is thought to stabilize the partial cationic charge at the reaction center in transition state 33.

Polar transition states 30 or 33 appear to be rather general for singlet carbene insertions. For example, Hammett analysis of the Rh carbenoid-mediated benzylic insertion of the arylcarbomethoxycarbene 34 into p-substituated ethylbenzene derivatives gave r ¼ 1:27 (vs. sþ).99 Dichlorocarbene insertions into the Si H bonds of silacumenes 35 are similarly characterized by r ¼ 0:63 (vs. s).100 In all cases, r < 0 implies the substrate carbonðdþÞ/carbene carbonðd Þ polarization depicted in 30 and reflective of electrophilic carbene attack on the C H or X H bond. The relatively low magnitude of r suggests an early transition state in which charge development at the substrate carbon is small. Note that r is smaller for CCl2 insertions into the Si H bond of 35 than the C H bond of 31; Si does not delocalize the developing positive charge in the transition state into the adjacent aryl ring as well as does C (Fig. 7.14).97

300 SINGLET CARBENES

Not all singlet carbene insertions are concerted. For example, Roth showed that the attack of singlet CH2 on the C Cl bond of CCl4 proceeded via initial chlorine abstraction to give a radical pair 36, which could either collapse to Cl3CCH2Cl (minor pathway) or diffuse to free radicals that followed other pathways. Chemically induced dynamic nuclear polarization (CIDNP) demonstrated that the Cl3CCH2Cl ‘‘insertion’’ product was largely formed by this two-step, singlet radical pair reaction.101 Analogous singlet abstraction–recombination mechanisms do not appear to occur with C H bonds.

More recently, Jones and co-workers102 found evidence for C H bond activation by appropriately situated carbon–carbon bonds; that is, C C hyperconjugative stabilization of dþ at the C insertion center. For example, the tertiary C H bonds in substrates 37–39 were particularly reactive toward CCl2; the interacting C C bonds presumed responsible for the C H reactivity are indicated by boldface (Fig. 7.15).

Figure 7.15

Moreover, the equatorial C H bond of 40 was six times more reative toward CCl2 than the axial C H bond of diastereomer 41. This observation is consistent with C C hyperconjugative stabilization that can operate in 40, but not in 42.102 Note that no CCl2 insertion occurred in the tertiary C H bonds a to the tert-butyl groups of 40 or 41 This lack of reactivity is presumably the result of adverse steric factors as well as lack of hyperconjugation (Fig. 7.16).

bond relative to the activating unit is crucial. Thus, the indicated C H bond of tricyclopropylmethane (42) in which the cyclopropyl groups enjoy significant rotational freedom, is five times less reactive toward CCl2 than is the indicated C H bond of substrate 38.102 On the other hand, the fixed cyclopropyl unit of 43 activated the a hydrogens toward CCl2 insertion.103 Dichlorocarbene attacked the

endo or cis C H bonds 4.3 times faster than the exo or trans C H bonds. This kinetic preference was attributed to better alignment of the endo C H bond with the neighboring electron-rich cyclopropyl C C bond (and the Walsh orbitals thereof ), and better stabilization of the partial positive charge that develops in the transition state for endo C H insertion.103

The LFP method has been used to determine absolute rate constants for intermolecular carbene insertion reactions. Given the more convenient diazirine precursor (14) available for C6H5CCl, as opposed to the phenanthrene precursor (15) of CCl2, as well as the directly observable character of C6H5CCl, LFP studies have

than the alkene additions of C6H5CCl summarized in Table 7.5. Other interesting substrates include cis,cis-1,3,5-trimethylcyclohexane (44), adamantane (37), and

cyclohexane (45). On a per-H basis, the rate constants for C6H5CCl insertion were 1:0 105, 1:3 105, and 0:06 105 M 1 s 1, respectively (Fig. 7.17).106

The tertiary C H bonds of 44 and 37 are slightly less reactive than the tertiary and benzylic C H of cumene, but they are 15–20 times more reactive than the secondary C H bonds of cyclohexane. These observations agree with the charge distributions depicted in transition states 30 and 33.

activation are comparable to those observed in C6H5CCl additions,57 and reflect the

entropy decrease that occurs when two reactant molecules combine to form a single product molecule.57,67,69

A kinetic isotope effect was measured for the insertion of C6H5CCl into the sec- C H (C D) bonds of cyclohexane and cyclohexane-d12; kH=kD 3:8 at 23 C.106

302 SINGLET CARBENES

This value is slightly larger than that for insertion of CCl2 into the benzylic, tertiary C H (C D) position of 2-butylbenzene (2.5 at 80 C)97 or cumene (2.6 at 120 C).98 All three reports, however, are consistent with appreciable C H or C D bond breaking in the transition state for insertion.

Calculations at the B3LYP/6-31G* level applied to the C6H5CCl-45 insertion afforded transition state 46, in which the target C H bond has lengthened from

39:8 e.u.) are not in very good agreement with the measured values (see above). Finally, a study of C6H5CCl insertion into the tertiary C H bond of substituted adamantanes 47 (Fig. 7.18, X ¼ H, OCH3, COOCH3, Cl, CN) gave a good Taft-type correlation between kins and sI, the inductive substituent constant of X.107 The s value ( 1.5) is again consistent with polar transition state 30, and indicates that significant electronic effects connect the C X dipole and the insertion site. These effects may be propagated through space, through the intervening s bonds, or by a combination of modalities.107 Computational studies at the B3LYP/6-31G* level provide an insertion transition state consistent with 30, 33, and 46. In particular, dþ on the adamantyl carbon was computed at þ0.18–0.20, and the negative charge on the carbenic carbon was 0.18 to 0.19 in the transition state for this electro-

philic insertion reaction.

X

H

47

Figure 7.18

2.2.2. Intramolecular Insertions: Rearrangements. These are signature reactions of singlet alkylcarbenes. Here, the intrinsic instability and high reactivity of the carbenes can be harnessed to the formation of highly strained olefins or multicyclic products, often granting access to ring systems not easily obtained by other means. Intramolecular insertions and rearrangements are therefore of great synthetic and mechanistic interest and have been frequently reviewed.108–115 Here we will briefly consider the kinetics and activation parameters of several representative intramolecular insertion reactions of carbenes, the role of ‘‘bystander’’ substituents, and the possible intervention of tunneling.

Alkylcarbenes generally lack useful UV signals for LFP studies, but they can be indirectly visualized by the pyridine ylide method in which their intramolecular reactions compete kinetically with capture of the carbene by added pyridine.

Reaction with pyridine leads to the formation of a UV-active pyridinium ylide.65 Rate constants for the alkylcarbene reaction(s) can be extracted from the intercept of the linear correlation of kobs for ylide formation versus the pyridine concentration.65 Consider first the 1,2-H shift that converts chloromethylcarbene (48) into vinyl chloride (Scheme 7.17). The LFP experiments show that the H shift occurs with k ¼ 1:2 3:0 106 s 1 in isooctane, cyclohexane, or dichloroethane at 21– 25 C.116 The rearrangement is fast, but not ultrafast; carbene (48) has a lifetime of 0.3–1 ms under these conditions. Variable temperature kinetics studies give Ea ¼ 4:9 kcal/mol (isooctane) or 6.8 kcal/mol (dichloroethane), with unfavorable

entropies of activation of 16 or 11.5 e.u., respectively.116b

.. ~H

48

Scheme 7.17

This seemingly simple rearrangement has been subjected to extensive theoretical analysis.117–119 Qualitatively, a three-centered transition state (Fig. 7.19, TS 49) can

be drawn for this reaction. The similarity to intermolecular carbene insertion TS 30 is apparent. The 1,2-H shift can be regarded as an intramolecular carbene insertion into an adjacent C H bond.

An important question is the charge distribution in 49, and the change in charge

Figure 7.19

on the three key atoms as carbene 48 goes to TS 49. Carbene 1,2-H shifts are usually called ‘‘hydride’’ shifts, although some high-level computations indicate that the migrating H may actually become more positive in TS 49 than it is in carbene 48 (e.g., by þ0.09 in heptane119). Negative charge does develop on the carbenic center

( 0.21 in 49) as electron density shifts away from the methyl carbon (þ0.14 unit) and the migrant H (þ0.09).118,119 The polar transition state is stabilized in polar

solvents, which increase the rate of rearrangement.

Because the methyl carbon of 48 becomes more positive in TS 49, replacement of its hydrogens by electron-releasing substituents will mitigate the charge increase and ‘‘drive’’ the H shift. Indeed, successive replacements of the hydrogens of

48 by methyl groups (affording carbenes 50 and 51, Fig. 7.19) increase k(1,2-H) to 1:3 108 s 1 (isooctane, 25 C)120 and >108 s 1 (isooctane, 90 C).121

These rate-enhancing methyl substituent effects have been termed ‘‘bystander assistance.’’122