Xavier Creary

Method for Assigning Structure of 1,2,3-Triazoles

1,4-Disubstituted-1H-1,2,3-triazoles 1 can easily be distinguished from the isomeric 1,5-disubstituted-1H-1,2,3-triazoles 2 by simple one-dimensional (13)C NMR spectroscopy using gated decoupling. The C(5) signal of 1 appears at δ ∼120 ppm, while the C(4) signal of 2 appears at δ ∼133 ppm. Computational studies also predict the upfield shift of C(5) of 1 relative to C(4) in 2.

Systematic Repression of β-Silyl Carbocation Stabilization

Solvolysis of 1-(trimethylsilylmethyl)cyclopropyl mesylate in CD(3)CO(2)D gives ring-opened products as well as methylenecyclopropane. The rate enhancement due to the beta-trimethylsilyl group is a factor of about 10(6). The large stabilizing effect of a beta-silyl group (which can cause rate enhancements of up to 10(12)) on the intermediate cation has been repressed. B3LYP/6-31G* computational studies indicate a carbocation stabilization energy of 16.6 kcal/mol. Rates of solvolyses of 1-phenyl-2-trimethylsilylcyclopropyl chlorides are enhanced by a factor of 10(3)-10(4). The intermediate cyclopropyl cation undergoes substantial ring opening since beta-silyl stabilization is not large (calculated stabilization energy of 12 kcal/mol). Solvolysis rates of 2-trimethylsilylbenzocyclobutyl derivatives are not significantly enhanced by the beta-trimethylsilyl group. Beta-silyl stabilization of benzocyclobutenyl carbocations generated in solution has been effectively eliminated due to antiaromatic considerations (calculated stabilization energy of 3.7 kcal/mol when R = Ph). While computational studies parallel solvolytic rate studies, they overestimate the extent of beta-trimethylsilyl stabilization of solvolytically generated carbocations.

γ-Silyl Cyclobutyl Carbocations

A series of 3-trimethylsilyl-1-substituted cyclobutyl trifluoroacetates have been prepared and reacted in CD(3)CO(2)D. Rate data indicate that the substrates with the trimethylsilyl group cis to the leaving group react with assistance due to gamma-silyl participation. Rate enhancements range from a factor of 209 for alpha-phenyl-substituted cations to 4.6 x 10(4) for alpha-methyl-substituted cations to >10(10) for the unsubstituted gamma-trimethylsilylcyclobutyl cation. Acetate substitution products are formed with net retention of stereochemistry. These experimental studies, as well as B3LYP/6-31G* computational studies, are consistent with the involvement of carbocations where the rear lobe of the gamma-Si-C bond interacts strongly with the developing cationic center. Solvolytic rate studies, as well as computational studies, suggest that the secondary gamma-trimethylsilylcyclobutyl cation is even more stable than the beta-trimethylsilylcyclobutyl cation, i.e., the gamma-silyl effect actually outweighs the potent beta-silyl effect. Although computational studies suggest the existence of certain isomeric cations, where the front lobe of the Si-C bond interacts with the cationic center, solvolytic evidence for the involvement of these front lobe stabilized cations is less compelling.

Oxygen-17 and oxygen-18 labeling studies by NMR. Mechanism of rearrangement of an .alpha.-thiophosphoryl trifluoroacetate to an .alpha.-phosphoryl thiotrifluoroacetate.

Acet~phenone-~~U and acetophenone-I8O have been condensed with hydrogen diethylthiophosphonate, and the resultant oxygen-labeled a-hydroxythiophosphonates, PhC(CH,)(*OH)PS(OEt),, 13, were converted to the labeled trifluoroacetates PhC(CH,)( *OCOCF3)PS(OEt)2, l-O and 1-l8O. Under acetolysis conditions, the major product from rearrangement of unlabeled 1 is the rearranged product PhC(CH,)(SCOCF,)PO(OEt),, 2. The mechanism of this rearrangement has been investigated using the labeled substrates 1-170 and 1-I8O. These substrates rearrange under acetolysis conditions to give a labeled product, 2 * , which has 80% of the label incorporated in the phosphoryl group and 20% of the label incorporated in the carbonyl group. In the case of 1-170, the label position was determined directly by I7O NMR spectroscopy. The acetolysis of llSO was also directly monitored by ,lP NMR where the chemical shift of phosphorus bonded to I6O differs from that of phosphorus bonded to I80. These complimentary labeling studies rule out a concerted mechanism for the formation of 6 , the key intermediate in this rearrangement. A k A mechanism, involving neighboring thiophosphoryl participation leading to an ion pair, where internal return of trifluoroacetate occurs at phosphorus, is the most probable mechanism leading to formation of the intermediate 6. Internal return of trifluoroacetate at phosphorus does not result in complete oxygen scrambling. Capture of the oxygen that was originally bonded to the incipient ionization center is 4 times more probable than capture of the more remote of the functionally nonequivalent trifluoroacetate oxygen atoms in the ion pair. Acetolysis of 1-I8O in the presence of unlabeled thiol PhC(CH,)(SH)PO(OEt),, 3, gave no incorporation of this unlabeled material in the product 2-*O. This study shows that the subsequent rearrangement of 6 to 2 is an intramolecular process not involving free thiol 3. Intramolecular trifluoroacetyl group transfer, after opening of 6 , offers a reasonable rationale for the formation of 2. These studies illustrate the utility of O NMR and 31P NMR for direct determination of the position of a labeled oxygen in mechanistic studies. We recently reported that the a-thiophosphoryl trifluoroacetate 1 reacts in acetic acid to give the products 2-5. The major product (63%) was the isomeric thiotrifluoroacetate 2. In this transformation, the thiophosphoryl group of 1 had been converted to an 0-phosphoryl group in 2. Also produced was a smaller amount (27%) of the deacetylated rearranged thiol 3. We have concluded YH3 R FH3 ;I Ph-~-PP(OE112 + Ph-c-p(OEt)2 I

3-Trimethylsilylcyclobutylidene. The γ-Effect of Silicon on Carbenes

3-Trimethylsilylcyclobutylidene was generated by pyrolysis of the sodium salt of the tosylhydrazone derivative of 3-trimethylsilylcyclobutanone. This carbene converts to 1-trimethylsilylbicyclobutane as the major product. A labeling study shows that this intramolecular rearrangement product comes from 1,3-hydrogen migration to the carbenic center and not 1,3-silyl migration. Computational studies show two carbene minimum energy conformations, with the lower energy conformation displaying a large stabilizing interaction of the carbene center with the rear lobe of the C3-Si bond. In this conformation, the trimethylsilyl group cannot migrate to the carbene center, and the most favorable process is 1,3-hydrogen migration. When the carbene is generated photochemically in methanol, it reacts by a protonation mechanism giving the highly stabilized 3-trimethylsilylcyclobutyl carbocation as an intermediate. When generated in dimethylamine as solvent, the carbene undergoes preferred attack of this nucleophilic solvent from the back of this C-Si rear lobe stabilized carbene.

Photochemical Behavior of Cyclopropyl-Substituted Benzophenones and Valerophenones

p-Cyclopropylbenzophenone, 20, gives no photoreduction when irradiated in i-PrOH solvent. This is a general phenomenon and a number of cyclopropyl-substituted benzophenones, including 4-(endo-6-bicyclo[3.1.0]hexyl)benzophenone, 19, 4-(cis-2,3-dimethylcyclopropyl)benzophenone, 21, 4-(cis-2-vinylcyclopropyl)benzophenone, 22, and 4-(endo-7-bicyclo[4.1.0]hept-2-enyl)benzophenone, 23, also fail to undergo photoreduction. Instead these latter compounds undergo cis-trans isomerization when irradiated. A mechanism involving formation of an (n, π*) triplet, which subsequently fragments the strained cyclopropane bond to give a lower energy and unreactive open triplet, has been suggested. p-Cyclopropylvalerophenone, 25, and p-(endo-6-bicyclo[3.1.0]hexyl)valerophenone, 24, also undergo photoisomerization and fail to undergo the Norrish Type II photoreactions. Triplet energy dissipation by fragmentation of the cyclopropane bond is also proposed. In addition to the Norrish Type II reaction, p-cyclobutylvalerophenone, 27, undergoes a photofragmentation to give ethylene and p-vinylvalerophenone, 60, by an energy dissipation mechanism involving a 1,4-biradical derived from cyclobutane bond fragmentation.

γ-Silyl-Substituted Norbornyl Carbocations and Carbenes

endo-2-Trimethylsilyl-anti-7-norbornyl triflate undergoes solvolysis reactions 1.8 × 10(4) faster than 7-norbornyl triflate in CD3CO2D and 1.3 × 10(5) times faster in CF3CH2OH. The exclusive substitution products with retained stereochemistry point to a significantly stabilized γ-trimethylsilyl carbocation intermediate. The endo-2-trimethylsilyl-7-norbornyl carbene gives a major rearrangement product where the trimethylsilyl-activated hydrogen migrates to the carbenic center. This rearrangement product implies stabilization of the carbene by the γ-trimethylsilyl group. Isodesmic computational studies (M062X/6-311+G**) indicate that the endo-2-trimethylsilyl-7-norbornyl cation is stabilized by 16.2 kcal/mol and that the endo-2-trimethylsilyl-7-norbornyl carbene is stabilized by a smaller factor of 1.8 kcal/mol. By way of contrast, anti-7-trimethylsilyl-endo-2-norbornyl mesylate undergoes solvolysis in CD3CO2D only 2.6 times faster than endo-2-norbornyl mesylate and 9.4 times faster in CF3CH2OH. The substitution products have only partially retained stereochemistry, and significant rearrangements are observed. The anti-7-trimethylsilyl-2-norbornyl carbene gives a rearrangement product via 1,3-hydrogen migration of the C6 hydrogen, which is completely analogous to the behavior of the unsubstituted 2-norbornyl carbene. Isodesmic calculations show that the anti-7-trimethylsilyl-2-norbornyl cation is stabilized by only 3.2 kcal/mol relative to the 2-norbornyl cation, and the corresponding anti-7-trimethylsilyl-2-norbornyl carbene is stabilized by a negligible 0.9 kcal/mol.

Cobalt- and Silver-Promoted Methylenecyclopropane Rearrangements

The rate of the methylenecyclopropane rearrangement is enhanced by an alkyne-Co2(CO)6 complex bonded to the para position of a benzene ring. This is explained by a stabilizing effect on the transition state leading to the biradical intermediate. Computational studies indicate that the benzylic-type biradical intermediate is stabilized by a delocalization mechanism, where spin is delocalized onto the two cobalt atoms. Silver cation also enhances the rate of the methylenecyclopropane rearrangement. Computational studies suggest that silver cation can also stabilize a benzylic radical by spin delocalization involving silver. In the case of the silver-promoted reactions, the rate enhancements in a series of aryl-substituted methylenecyclopropanes correlate with σ+ values. The question remains open as to whether the silver-catalyzed methylenecyclopropane rearrangement proceeds via an argento-stabilized biradical or whether the reaction involves an argento-substituted allylic cation.

γ-Trimethylsilylcyclobutyl Carbocation Stabilization

A series of isomeric 3-trimethylsilyl-1-arylcyclobutyl carbocations, 10 and 11, where the cross-ring 3-trimethylsilyl group has the potential to interact with the cationic center, have been generated under solvolytic conditions. When the cationic center can interact with the rear lobe of the carbon-silicon bond, rate enhancements become progressively larger as the substituent on the aryl group becomes more electron-withdrawing. When the potential interaction with the trimethylsilyl group is via a front lobe interaction, there is minimal rate enhancement over the range of substituents. Computational studies have also been carried out on these cations 10 and 11. Calculated trimethylsilyl stabilization energies progressively increase with electron-withdrawing character of the aryl groups when the trimethylsilyl interaction is via the rear lobe. By way of contrast, there are minimal changes in stabilization energies when the potential trimethylsilyl interaction is via the front lobe of the carbon-silicon bond. These computational studies, along with the solvolytic studies, point to a significant rear lobe 3-trimethylsilyl stabilization of arylcyclobutyl cations. They also argue against any front lobe stabilization of the isomeric arylcyclobutyl cations.

Reductive cleavage of succinic esters. A method for the introduction of acetic acid fragments

Diels–Alder addition of maleic or fumaric esters to 1,3-dienes, followed by catalytic reduction and treatment with sodium in liquid ammonia at –78°, which promotes a solvent dependent reductive cleavage of the carbon–carbon σ bond of the succinic ester fragment, provides a general method for the preparation of derivatives of suberic acid.