Carbenes dimethoxycarbene

In contrast to the reactivity of most simple carbenes, dimethoxycarbene does not readily undergo addition to alkenes unless the alkene is substituted with electron-withdrawing substituents. Propose an explanation for this behavior. 

Carbene reactivity is strongly affected by substituents.117 Various singlet carbenes have been characterized as nucleophilic, ambiphilic, and electrophilic as shown in Table 10.2 This classification is based on relative reactivity toward a series of both nucleophilic alkenes, such as tetramethylethylene, and electrophilic ones, such as acrylonitrile. The principal structural feature that determines the reactivity of the carbene is the ability of the substituent to act as an electron donor. For example, dimethoxycarbene is devoid of electrophilicity toward alkenes because of electron donation by the methoxy groups.118... 

Besides isocyanides, Nair and coworkers also used carbenes to add to alkynes such as DMAD (9-90) leading to 1,3-dipoles, which can be trapped in a formal 1,3-dipolar cycloaddition (Scheme 9.21) [61]. Thus, the dimethoxycarbene 9-99, generated in situ through thermolysis of 9-98, reacts with DMAD (9-90) to give the dipole 9-100, which adds to an aldehyde 9-97 or a ketone. As the final product, dihydrofurans 9-101 are obtained in good yields. 

Indeed, such donation is calculated to stabilize singlet dimethoxycarbene by 76 kcal/mol relative to the corresponding triplet.93 The electron donation also modulates carbenic reactivity 78 a strong electron donor on Q raises both the carbene s HOMO and LUMO energies, thereby increasing the carbene s nucle-ophilicity while rendering its LUMO less accessible to nucleophiles (decreasing its electrophilicity).94 These consequences are illustrated by 69 and the related structures in Scheme 6. 

These findings, and extensive subsequent work, are consistent with a singlet ground state for this species. The chemical reactivity of these carbenes towards olefins can be related empirically but quantitatively to the electronic properties of the substituents (Moss et al., 1977 Moss, 1980). An extreme example is dimethoxycarbene which does not exhibit at all the electrophilic properties normally associated with the vacant non-bonding orbital of a singlet carbene (Lemal et al., 1966). These findings are easily understood by... 

The computed values of Aee and Aen also predict that dimethoxycarbene should be a nucleophilic carbene. Experimentally, dimethoxycarbene does not add at all to electron-rich alkenes (preferring to dimerize instead), but does add readily to electron-poor methyl acrylate and acrylonitrile." Many other nucleophilic reactions of (CH30)2C and related dialkoxycarbenes have been investigated and reviewed by Warkentin." ... 

At the opposite end of the philicity spectrum, nucleophilic carbenes have proven useful in synthesis. Warkentin" pioneered the thermolysis of oxadiazolines as precursors for (CH30)2C and related dioxacarbenes (Scheme 7.3). Dimethoxycarbene generated from an oxadiazoline undergoes a variety of intermolecular reactions." One example is the ring enlargement of strained cyclic ketones, for example, cyclo-butanone. In this reaction, the nucleophilic carbene initiates the ring expansion by... 

Although electrophilic carbenes react with the sulfur atom of CS double bonds, dimethoxycarbene reacts at the carbon atom.10 A review commentary covers the limited range of literature available covering 2,2,4,4-tetramethyl-l,3-cyclobutanedithione, diarylthiones, o-methyl thiobenzoate, methyl dithiobenzoate, and dimethyl xanthate. 

The synthetic reactions of nucleophilic carbenes have been reviewed.11 Isonitriles, dimethoxycarbene, and NHCs are covered. The review focuses on the 1,3-dipolar cycloaddition reactions made possible when the nucleophilic carbene reacts with electrophiles such as dimethylacetylene dicarboxylate. Such reactions were also the subject of research papers during 2005 (see the section on nucleophilic and basic carbenes). 

In practice, donor substituents make it possible actually to isolate a range of carbenes 4.105. With somewhat less stabilisation, the carbene 4.106, although it is only found as a reactive intermediate, is exceptionally easy to form. It is the key intermediate in all the metabolic steps catalysed by thiamine coenzymes, and its reactions are characterised by its nucleophilicity. Similarly, dimethoxycarbene 4.107 reacts as a nucleophile with electrophiles like dimethyl maleate to give the intermediate 4.108, and hence the cyclopropane 4.109, but it does not insert into unactivated alkenes. 

Chloro(methoxy)- and chloro(phenoxy)carbenes, which are generated from the diazirine precursors, behave as ambiphiles in additions to alkenes, exhibiting high reactivities toward both electron-poor and electron-rich olefins. Methoxy(phenyl)- and ferrocenyl(methoxy)methylenes have been transferred in a stereospecific manner from transition metal complexes of these species to electron-deficient alkenes. Irradiation of benzocyclobutanedione with UV light induces a rearrangement of the cyclic a-diketone to 17, which has been trapped by alkenes in good yields " . Thermolysis of 18 gives rise to nucleophilic dimethoxycarbene, which has been intercepted by electron-deficient olefins or by styrene derivatives. 

In the path b process, the addition of a heterosubstituted carbene to an olefin is governed by the reactivity of each component. Bis-thiomethyl- and bis-thiobenzylcarbenes add only to electron-rich olefins, whereas dimethoxycarbene adds primarily to electron-poor systems. Ambiphilic carbenes such as phenoxychlorocarbene and methoxychlorocarbene add to a wide range of double bonds. Table 16 lists the cyclopropanone equivalents which have been prepared in this manner. 

The imine reaction with carbenes is also efficient when the carbonyl group participating in oxazoline ring formation is incorporated in an imine, rather than a carbene, component. This is exemplified by a reaction of dimethoxycarbene with acylimines, resulting in good yields of substituted oxazoles 545, as well as by a reaction of difluorocarbene with imine 13, affording oxazoline 14 in 62% yield (79IZV1826). 

Reactions of other carbenes with carbonyl compounds, resulting in the formation of dioxolanes, have received much less study. Dimethoxycarbene,... 

Thermal decomposition of 7,7-dialkoxynorbornadiene derivatives in the presence of an alkene requires rather high temperatures ( 125°C) l,2,3,4-tetrachloro-7,7-dimethoxy-5-phenylbicyclo[2.2.1 ]hepta-2,5-diene is the most often applied source of dimethoxycarbene. Electrophilic alkenes such as )- and (Z)-but-2-enedioates and cinnamates, styrene derivatives, " 1-phenylbuta-l,3-diene etc. undergo addition of this carbene across the double bond to give 1,1-dimethoxycyclopropanes 2. 

This type of Cj-extrusion reaction has been predominantly of theoretical interest, especially with respect to the correlation of carbene reactivity with the structure of the precursor and the method of cleavage/ However, some attempts to use this Cj-extrusion method to generate certain carbenes for synthetic uses have also been reported. Thus, hexamethoxycyclopropane (5) has been probed as a potential source of dimethoxycarbene (6). 

Nucleophilic carbenes like dimethoxycarbene do not undergo cycloaddition reactions with simple alkenes, nor do they insert into C—H bonds. Electrophilic carbenes, on the other hand, like the bis(methoxycarbo-nyl)carbene 4.212, with a low-energy LUMO, react with molecules like alkenes that have a high-energy... 

The insertion of a carbene into an alkene is a result of the simultaneous interaction of the HOMO of the alkene with the LUMO of the carbene or the LUMO of the alkene with the HOMO of the carbene. It is the HOMO of a nucleophilic carbene that interacts predominantly with the LUMO of the alkene and, likewise, the LUMO of an electrophilic carbene that interacts predominantly with the HOMO of the alkene. In the case of the highly nucleophilic dimethoxycarbene, the interaction of HOMO of the carbene with the LUMO of the alkene is so very strong that it gives zwitterionic intermediates such as 151, which results in the loss of stereochemistry in going from a c/.v-alkene to a -cyclopropane. With the less nucleophilic carbenes, the geometrical integrity of the alkene is retained in the product. Additionally, nucleophilic carbenes do not insert Oc-h bonds. 

The kinetic isotope effect k /kj) found by Moss et al. (1988) for attack of the significantly nucleophilic dimethoxycarbene on CH30H(D) suggests a substantial OH to carbene proton transfer during this reaction. 

For example, dimethoxycarbene is devoid of electrophihcity toward alkenes because of electron donation by the methoxy groups. A methoxy group also can be expected to stabilize a carbene, by interaction of the p orbital of the central carbon atom with a lone pair of electrons on the oxygen atom (Scheme 5.2). 

The addition of dimethoxycarbene to olefin, only a recently discovered reaction, has been subjected to detailed mechanistic study and the reaction stereochemistry has been unequivocally determined with the aid of labelled substrates. Thermally generated dimethoxycarbene undergoes stereospecific addition to P-deuteriostyrenes with no observable isotope effect for carbene selectivity between labelled and unlabelled olefin. This behaviour is most compatible with the concerted addition of a... 

---