Reactive Intermediate Chemistry

304 SINGLET CARBENES

The generally accepted order of 1,2-shift tendencies or ‘‘migratory aptitudes’’ for alkylcarbenes is (R) ¼ H > C6H5 > CH3.18,122,123 However, taking bystander

assistance by substituents G1 and G2 into account, Nickon suggested that the intrinsic migratory aptitude order is C6H5 > H > CH3.122 This conclusion has been supported computationally.118 The point is that bystander assistance by C6H5 (Scheme 7.18, 52, G1 ¼ C6H5; R ¼ H) stabilizes positive charge at the migration origin and accelerates the 1,2-H shift, whereas there is no comparable stabilization and drive for C6H5 shift when G1 ¼ H and R ¼ C6H5. Nickon has provided numer-

ical ‘‘bystander assistance factors’’ for various groups (G) in 1,2-H shift rearrangements.122

Scheme 7.18

Bystander substituents directly influence the migrating group at the migration origin. We can also identify effects of ‘‘spectator substituents’’ (X in 52) at the migration terminus. Spectator groups ‘‘tune’’ the electronic environment at the divalent carbon through resonance and inductive effects and modulate its electrophilicity, reactivity, and lifetime. Spectator substituents alter the rates of 1,2-rear- rangements but do not change the order of migratory aptitudes or bystander assistance effects.114 Computational studies show that the activation energies for 1,2-H shifts in CH3CX are linearly related to the electron donating power ðs RÞ of spectator X;123 Ea increases as X becomes a better electron donor.

Computational studies of the CH3CCl to vinyl chloride rearrangement

(Scheme 7.17) provide an activation energy that can be compared to those measured by LFP experiments.118,119 The gas phase computed Ea is 11.5 kcal/ mol,118,119 which is reduced to 9.3 kcal/mol in (simulated) heptane.119 The

experimental value in isooctane is 4.9 kcal/mol.116b Some of the 4.4 kcal/mol difference between the computed and observed Ea can be narrowed if quantum

mechanical tunneling (QMT) is included in the calculations: The migrant H atom can ‘‘tunnel’’ through the activation barrier as well as climb over it.116b,117,119 The

QMT considerations reduce the computed Ea for 1,2-H shift to 6.9 kcal/mol in heptane119 in reasonable agreement with the observed value.

Charge development in TS 49 makes the transition state more polar than CH3CCl itself and subject to stabilization by a polar solvent. Indeed, the computed Ea for the rearrangement of CH3CCl to vinyl chloride in dichloroethane (including tunneling) is 6.0 kcal/mol, 0.9 kcal/mol less than in heptane,119 so, we expect the 1,2-shift to be faster in the more polar solvent. Such effects are rather general.124

Another well-studied 1,2-H shift is the rearrangement of benzylchlorocarbene (53) to (Z) and (E)-b-chlorostyrene (Scheme 7.19).110,114,125,126 In the 0–31 C tem-

perature range, k1;2-H 6 107 s 1 with Ea ¼4.5–4.8 kcal/mol in isooctane.127 At lower temperature (to 80 C) Arrhenius studies led to curved correlations of ln k1;2-H versus 1/T that were initially attributed to QMT.128 However, the intervention of competing reactions of 53 with solvent isooctane and with its precursor diazirine biased the kinetic results at lower temperatures and led to curvature in the Arrhenius plot.126 In tetrachloroethane, in which the 1,2-H shift of 53 is relatively

clean even at lower temperatures, a linear correlation of ln k1;2-H and 1=T was found from 3.2 to 71.4 C, affording Ea ¼ 3:2 kcal/mol and log A ¼ 10:0 s 1,126 in good

agreement with values determined in CHCl3.128 Although tunneling does not seem to be important in the 1,2-H shift of 53 in solution near ambient temperature,126 tunneling is dominant when the rearrangement occurs in Ar or Xe matrices at 10–30 K, because the ‘‘normal’’ activated process is vanishingly slow.129

The 1,2-H shift in 53 is of interest in connection with the possible intervention of kinetically significant carbene–alkene complexes and 1,2-H shifts that may occur in

excited states of the nitrogenous carbene precursor as well as in the carbenes.110,114,115 These questions will be further discussed in Section 2.4.

An important example of a 1,2-C migration (C C insertion) is the ring expansion of chlorocyclopropylcarbene (54) to 1-chlorocyclobutene (Scheme 7.20).127,130–132

The 1,2-C shift takes precedence over 1,2-H shift. Chloromethylenecyclopropane (55), the putative product of a 1,2-H shift, is not formed. Interaction of the electron-rich ‘‘bent’’ cyclopropane C C bond(s) with the vacant p orbital of carbene 54 leads to a more favorable rearrangement pathway than the alternative sC-H=P interaction leading to 55.

Scheme 7.20

In hydrocarbon solvents, k1;2-C ranges from 4 105–1:5 106 s 1, according to several measurements.130,131 The Ea has been variously reported as3:0 kcal=mol131 or 7.4 kcal/mol.130 The former value, measured by four different approaches, is probably the more reliable one. For comparison, the analogous rearrangement of cyclopropylfluorocarbene to 1-fluorocyclobutene occurs with

306 SINGLET CARBENES

k1;2-C ¼ 1:4 105 s 1; Ea ¼ 4:2 kcal/mol (pentane, 23 C).132 Note the spectator substituent effect; F is a better electron donor than C1, and therefore slows the 1,2-C shift and raises Ea, relative to 54.

The 1,2-C shift in 54 exhibits an unfavorable Sz ( 23 e.u.) that was attributed to dynamic effects.131 However, a very detailed theoretical study of this rearrangement is not in good agreement with the experimental results.119 The computed Ea (8.2 kcal/mol in simulated isooctane) is 5 kcal/mol higher than the experimental value, and the computed Sz is close to zero. With cyclopropylfluorocarbene, there are even larger disparities between the observed and computed activation parameters. The experimental measurements for cyclopropylfluorocarbene132 were reproduced119 with no significant change, so that reason(s) for the divergence between the measured and computed activation parameters remain unknown. An extraordinarily thorough discussion of the problem appears in Ref. 119.

We conclude this section with a brief consideration of dimethylcarbene [CH3CCH3 (56)], the simplest dialkylcarbene, in which a 1,2-H shift produces propene. Although methylene (CH2), and methylcarbene (CH3CH) are ground-state triplets, dimethylcarbene is computed to be a ground-state singlet: calculated sing-

let–triplet differential energies ( ES--T, kcal/mol) are CH2 (9), CH3CH (3–5), and 56 ( 1.4).14–18,22,23,133 As mentioned at the beginning of this chapter, the electron-

releasing methyl substituents stabilize a singlet carbene center (with its vacant, electronegative p orbital), relative to a triplet carbene center (with singly occupied

Cl substituent, which stabilizes CH3CCl by resonance electron donation into the carbene’s p orbital and thus slows the 1,2-H shift. The spectator CH3 substituent of 56 is a poorer electron donor than Cl and is less effective in stabilizing CH3CCH3, so that its 1,2-H shift is more rapid. However, the spectator methyl group of 56 strongly affects the 1,2-H shift relative to that of CH3CH. The computed Ea values for CH3CH and CH3CCH3 are 1.9 and 7.3 kcal/mol, respectively.133

The lifetime of 56 in hydrocarbon solvents at 25 C is only several nanoseconds, so that its intermolecular chemistry should be difficult to observe. Indeed, intermolecular C H insertion reactions of 56 are inefficient, although the carbene can be captured (competitively with 1,2-H shift) by insertions into O H or N H bonds or by addition to isobutene.135

The lifetime of 56 can be extended by deuteration: CD3CCD3 lives 3.2 times longer in pentane than does CH3CCH3. This longevity is the result of a substantial primary kinetic isotope effect where k1;2-H > k1;2-D.134b Tunneling is important here: the H shift occurs in part by tunneling, a pathway not as available to the D shift. On the other hand, polar solvents increase k1;2-H and decrease the lifetime of

56, in accord with the increase in charge stabilization in the 1,2-H shift transition state.134b

2.3. Singlet–Triplet Equilibration

As mentioned earlier, when the triplet and singlet states lie close together in energy, as they often do, one can expect equilibration and, possibly, reactions of both spin states. Except in special circumstances, the exothermicity of singlet reactions (remember that two new bonds can be formed from a singlet) gives the singlet a great advantage over the triplet. An impressive array of spectroscopic and theoretical tools has been brought to bear on the case of 2-naphthyl(carbomethoxy)carbene (57). A combination of LFP, time-resolved infrared (IR), and UV/vis and electron spin resonance (ESR) spectroscopies, carried out in five different laboratories in Japan, Switzerland, and the United States has clarified the picture in great detail.136a Photolysis of the diazo compound leads initially to the singlet state, which rapidly decays to the planar, ground-state triplet. Triplet carbene (57T) is mainly formed in the two geometries shown, reflecting the preference of the starting diazo compound for the (E,E) and (Z,E) forms. Photolysis of 57T at 515 nm leads to the perpendicular singlet state (57S). In the perpendicular geometry, the filled sp2 orbital of the divalent carbon can overlap with the p system of the carbonyl, and the destabilizing interaction between the empty 2p orbital of the carbene and this p system is minimized. At 12 K, or on photolysis at 450 nm, 57S reverts to 57T (Scheme 7.21).

Scheme 7.21

The infrared studies allow an estimation of the (solvent dependent) energy gap between the lower triplet 57T and the higher singlet 57S as only 0:2 0:1 kcal/mol. Computations find a larger gap (4.5 kcal/mol), but computations do not reflect the differential stabilization of the singlet (with its cation-like empty orbital) state by solvent.

In this case (but not all others, see Section 2.4), it is the singlet carbene that is responsible for intramolecular carbon–hydrogen insertion to give 58 and Wolff rearrangement to give 59 (Scheme 7.22). Note that direct formation of 59 from the favored (E,E) and (Z,E) forms of the diazo compound is unlikely because the migrating methoxy group would have to displace the departing nitrogen from

Scheme 7.22

the front side. This kind of phenomenon was first noticed many years ago by Kaplan and Meloy.136b

Although the equilibration of singlets and triplets has been many times inferred from classical studies of reaction products, and taken as a given by the community, this tour de force work for the first time allows the direct observation of the many interrelated reactive intermediates involved when a carbene precursor is irradiated.

2.4. Carbene Mimics

Throughout this chapter, we have almost always ignored the role of the carbene precursor. Carbenes are generally made from diazo compounds, or from a variety of surrogate diazo compounds including diazirines, tosylhydrazone salts, and aziridyl imines, all of which probably decompose through nonisolable diazo compounds. Not surprisingly, it turns out that diazo compounds have a rich chemistry of their own, especially when irradiated. Moreover, that chemistry often closely resembles the reactions of carbenes. Much of intramolecular ‘‘carbene chemistry’’ is, in fact, diazo compound chemistry.

As early as 1964 Frey observed that the ratio of 1,1-dimethylcyclopropane and 2-methyl-2-butene, the products from intramolecular reactions of tert-butyl diazomethane, was strongly dependent on the method used to decompose the diazo compound (Table 7.6).137 The response of the community of carbene chemists was largely to ignore Frey’s data, and to continue to treat diazo compounds as uncomplicated sources of carbenes. So they may be in intermolecular reactions, but they are far from benign in intramolecular chemistry, as we shall now see.

Modarelli and Platz and his co-workers138 used the pyridine ylide technique65 to determine that much of the intramolecular chemistry attributed to simple alkylcarbenes such as methylcarbene and dimethylcarbene is, in fact, owing to reactions of excited nitrogenous precursor molecules. As we have seen, many carbenes, even those with lifetimes so short that they cannot be visualized directly by LFP experiments, can be trapped by pyridine to form ylides, which absorb strongly in the conveniently accessible visible region of the electromagnetic spectrum. As the concentration of pyridine is increased, the signal coming from the ylide saturates. Under such conditions every carbene formed from the starting material is converted into an ylide. If products of ‘‘carbene’’ reactions persist under such conditions, they

a Tetrahydrofuran ¼ THF.

must in reality owe their formation to some other intermediate, presumably the precursor in some form. In this fashion, it has been shown that photolysis of dimethyldiazirine yields an excited state that forms trappable dimethylcarbene in only low

yield. Most of the propene that is formed as the major product comes from direct reaction of the excited state.134b,138 This phenomenon is general: In the photoche-

mical decompositions of nitrogenous precursors to carbenes, the chemistry resulting from many alkylcarbenes has been shown to be accompanied by significant amounts of precursor chemistry (Scheme 7.23). Other, ring-opened excited states may also intervene in the reaction sequence of Scheme 7.23. Occasionally, even thermal reactions involve precursor chemistry.139

Scheme 7.23

A completely different approach was used to probe the reactivity of tert-butyl- carbene, one of Frey’s original examples.137 Table 7.6 shows the varying products of thermal and photochemical decomposition of the diazo compound. It would appear that carbon–hydrogen insertion and carbon–carbon insertion are about equally facile in the carbene presumed to be formed in photolytic reactions. Even in 1964, this observation should have seemed strange (as it clearly did to

310 SINGLET CARBENES

Frey), as there was no known example of an intermolecular carbon–carbon insertion.1 The ensuing decades have not revealed such a reaction, despite some hard searching.140 Why should the intramolecular version of carbon–carbon insertion compete so favorably with carbon–hydrogen insertion? It doesn’t. Two alternative sources of tert-butylcarbene, photochemical decomposition of 60141a and deoxygenation of pivaldehyde (61)141b have shown that the real carbene chemistry is that found in the thermal decomposition of the diazo compound (Scheme 7.24; cf. with Table 7.6).141 Photochemical decomposition, as Frey suspected in 1964, is complicated by a substantial direct rearrangement to 2-methyl-2-butene in the excited diazo compound, mimicking a carbon–carbon insertion of the carbene.

Scheme 7.24

A similar story attends the chemistry of cyclopropylcarbenes. In the 1960s it was shown that cyclopropyl methyl diazomethane gives almost exclusively the product of apparent carbon–carbon insertion.142 Surely we are now suspicious, and rightly so, as neither photolysis of 62 nor deoxygenation of cyclopropyl methyl ketone reproduces these results. Instead, carbon–hydrogen insertion dominates (Scheme 7.25). Once again, a direct reaction of photoexcited diazo compound appears to be the dominant source of the product of ring expansion (carbon–carbon insertion).

Huang and Platz143 used a variation of the pyridine ylide technique65 to determine that ring expansion was a property of the parent diazo compound, (tert-butyl)- cyclopropyl diazomethane (63) not (tert-butyl)cyclopropylcarbene itself. They used increasing amounts of 2,3-dimethyl-2-butene to scavenge the carbene formed on photolysis of the cyclopropyldiazirine. The yield of ring expanded product, 3-tert-butylcyclobutene, was not diminished significantly with increasing alkene concentration, thus showing that ring expansion, again a putative carbon–carbon insertion, was not the result of a carbene reaction. If the cyclobutene were a carbene product, its yield would fall off as carbene reacted with the alkene. Once again, direct ring expansion of a nitrogenous precursor is implicated. The take home

CH3

h ν

33% 67% diglyme-d14

62

Scheme 7.25

lesson here is that one must always consider whether precursor chemistry is masquerading as carbene chemistry, especially when carbon–carbon insertion apparently leads to the product (Scheme 7.26).

C(CH3)3

Scheme 7.26

A carbene mimic was also at the center of a rather long-standing controversy on the role of carbene–alkene complexes as potential intermediates in carbene reactions. The arguments began when it was found that photolysis of benzylchlorodiazirine led to (Z)- and (E)-b-chlorostyrenes through two intermediates.There was no simple linear relationship between the yields of the two styrenes and the concentration of an added trapping agent, 2-methyl-2-butene. Instead, the plots were curved and this observation requires two intermediates. It was originally suggested that the carbene and a complex between carbene 53 and the alkene were the two intermediates (Scheme 7.27).125

Scheme 7.27

Complexes were also considered for other carbenes144 and even suggested for reactions in alkane solution(!)128 A counterproposal, backed by the inability of theory to find support for such stable complexes,67b held that the second source was not the carbene–alkene complex but instead was the diazo compound, formed from isomerization of excited diazirine.145 Other LFP studies reinforced the need for two

intermediates, but could not finally resolve the question of carbene complexes versus diazo compound.125,127a,128 However, the question is now settled in this case,

and, by extension, in others as well. No curved plots appear when the benzylchlorocarbene is produced from 64, a non-nitrogenous source (Scheme 7.28).146 The second source of the styrenes is not a carbene–alkene complex; this notion is dead, at least for benzylchlorocarbene.

Scheme 7.28

All this is not to say that dialkylcarbenes are incapable of the reactions formerly attributed to them exclusively. They often—usually—are able to do the reactions, even in cases in which diazo compound chemistry pre-empts their doing so. For example, homocubylidenes (65) are not the first-formed intermediates from the diazohomocubane precursor (66). The bridgehead alkenes, homocubenes (67) are. However, it was possible to use a complex kinetic analysis involving both the pyridine ylide technique65 and the alternative hydrocarbon precursor 68 to show that in the parent system the two reactive intermediates 65 and 67 are in