Carbene Rearrangement Research Articles

Generation and interception of bicyclo[3.2.1]oct-2-yne: an experimental and theoretical mechanistic study.

Bicyclo[3.2.1]oct-2-yne was generated from the Fritsch-Buttenberg-Wiechell rearrangement of 2-norbornylidene carbene. The rearrangement preferentially involves migration of a tertiary carbon over a secondary carbon, a trend that contrasts with rearrangements of acyclic carbenes and which may be attributable to hyperconjugative effects promoted by the bridged structure of the carbene.

Rh-Catalyzed [2,3]-Sigmatropic Rearrangement of Alkynyl Carbenes with Allyl Sulfides to Access Sulfide-Substituted 1,5-Enynes.

This study describes the development of Rh-catalyzed [2,3]-sigmatropic rearrangement of alkynyl carbenes with allyl sulfides. The protocol exhibits equitable functional group tolerance and allows the formation of a variety of synthetically valuable sulfide-substituted 1,5-enyne products. To the best of our knowledge, this is the first example of [2,3]-sigmatropic rearrangement of alkynyl carbenes. DFT analysis supports the involvement of rhodium carbene generation, sulfonium ylides formation, and [2,3]-sigmatropic rearrangement pathway.

Ir(I)-Catalyzed Synthesis of Furanones from Vinyl Sulfoxonium Ylides.

A method for the synthesis of allyl substituted γ-butenolides via carbonyl ylide rearrangement of vinyl sulfoxonium ylide-derived carbenes has been developed. At rt, the mechanism involves a carbonyl ylide generation/allyloxy furan formation/[3,3]-sigmatropic rearrangement/isomerization sequence for the generation of 3-allyl butenolides. At 70 °C, instead of the final isomerization step, the resulting [3,3]-sigmatropic rearrangement product undergoes further [3,3]-sigmatropic rearrangement to produce 5-allyl butenolide. In the absence of the catalyst, the reaction affords a diene via [2,3]-sigmatropic rearrangement.

Alex Nickon

Alex Nickon, 93, died March 24, 2021, in Copper Canyon, Texas. “Nickon was an authority on the study of fundamental organic reaction mechanisms, especially of carbocation and carbene rearrangements. He is perhaps best known for his elucidation of homoenolization. In nearly 40 years at Johns Hopkins University, Alex was an exemplary educator and mentor, and he gave selflessly to the broader chemical community through service to the American Chemical Society in several capacities: as a senior editor of the Journal of Organic Chemistry and for nearly 20 years as the American executive editor of Tetrahedron . Both colleagues and former students agree that Alex was eternally positive and ever ready with measured, sage advice. In addition to these admirable professional and personal qualities, it is little known that Alex was also an accomplished magician.”—Craig Townsend, colleague Most recent title: Professor Emeritus of chemistry, Johns Hopkins University Education: BS, chemistry, University

Systematic Evaluation of 1,2-Migratory Aptitude in Alkylidene Carbenes.

Alkylidene carbenes undergo rapid inter- and intramolecular reactions and rearrangements, including 1,2-migrations of β-substituents to generate alkynes. Their propensity for substituent migration exerts profound influence over the broader utility of alkylidene carbene intermediates, yet prior efforts to categorize 1,2-migratory aptitude in these elusive species have been hampered by disparate modes of carbene generation, ultrashort carbene lifetimes, mechanistic ambiguities, and the need to individually prepare a series of 13C-labeled precursors. Herein we report on the rearrangement of 13C-alkylidene carbenes generated in situ by the homologation of carbonyl compounds with [13C]-Li-TMS-diazomethane, an approach that obviates the need for isotopically labeled substrates and has expedited a systematic investigation (13C{1H} NMR, DLPNO-CCSD(T)) of migratory aptitudes in an unprecedented range of more than 30 alkylidene carbenes. Hammett analyses of the reactions of 26 differentially substituted benzophenones reveal several counterintuitive features of 1,2-migration in alkylidene carbenes that may prove of utility in the study and synthetic application of unsaturated carbenes more generally.

Uncommon carbene-to-azole ligand rearrangement of N-heterocyclic carbenes in a ruthenium system.

The study of non-innocent behavior of NHCs (NHCs = N-heterocyclic carbenes) has great implications for NHC-involved catalysis. Herein, we report a new type of NHC-to-azole rearrangement, during which process the carbene backbone and the substituent are both non-innocent. To the best of our knowledge, this work also presents the first example of NHC-to-azole rearrangements for aryl-substituted NHCs.

Tricyclo[2.1.0.02,5]pent-3-ylidene: Stereoelectronic Control of Bridge-Flapping within a Nonclassical Nucleophilic Carbene.

Tricyclo[2.1.0.02,5]pent-3-ylidene is a carbene foreseen to rearrange to pyramidane (c-C4H4)C, a highly strained molecule featuring an inverted C atom. Modeling of the carbene, using the (U)MPWB1K/cc-pVTZ//(U)MPWB1K/6-311G(d) theoretical model, indicated a large singlet–triplet energy gap (ΔES–T = −45 kcal/mol), a high gas-phase proton affinity (PA = 258 kcal/mol), and a preference for electron-poor alkenes. These properties are consistent with those of nucleophilic carbenes. Structural differences between the Cs-symmetric singlet (ωflap = ±44 deg) and C2v-symmetric triplet (ωflap = 0 deg) stem from nonclassical electron delocalization in the former and the lack thereof in the latter. Degenerate bridge-flapping of the singlet’s main bridge, which comprises the reactive divalent C3 atom, is computed to be slow due to a high activation barrier of the C2v-symmetric transition state (TS) (Ea = 17 kcal/mol). The position of the conformeric equilibrium is subject to stereoelectronic control. 1-Substituted derivatives of the carbene (R ≠ H) are sensitive to σ inductive effects. A proximal conformation is preferred when R is electron-donating and a distal one is favored when R is electron-withdrawing. Finally, carbene rearrangements via 1,2-C atom shift or enyne fragmentation were computed. The C2v-symmetric bridge-flapping TS has the proper geometry to initiate enyne fragmentation.

Hydrogen tunnelling in the rearrangements of carbenes: the role of dynamical calculations.

Tunnelling controlled chemical reactions are those which preferably proceed through pathways with high but narrow potential energy barriers, via quantum tunnelling, resulting in a product that would be disfavoured classically. These reactions are very sensitive to barrier width, height and temperature and so dynamical theoretical methods are required to describe these processes. Recent experimental work on charge-tagged phenyl pyruvic acid derivatives has found, in contrast to similar systems, no evidence of tunnelling control. Using semiclassical transition state theory, we rationalise these results and find tunnelling is significant in this system.

MnI /AgI Relay Catalysis: Traceless Diazo-Assisted C(sp2 )-H/C(sp3 )-H Coupling to β-(Hetero)Aryl/Alkenyl Ketones.

An unprecedented MnI /AgI -relay-catalyzed C(sp2 )-H/C(sp3 )-H coupling of (vinyl)arenes with α-diazoketones is reported, wherein the diazo group was exploited as a traceless auxiliary for control of regioselectivity. Challenging β-(hetero)aryl/alkenyl ketones were obtained through this operationally simple approach. The cascade process merges denitrogenation, carbene rearrangement, C-H activation, and hydroarylation/hydroalkenylation. The robustness of this method was demonstrated at preparative scale and applied to late-stage diversification of natural products.

Photochemistry of the Stilbenes in Methanol. Trapping the Common Phantom Singlet State.

A comparative study of the photochemistry of cis- and trans-stilbene in methanol shows that both isomers undergo methanol photoaddition giving similar yields of α-methoxybibenzyl in competition with cis-trans photoisomerization. Methanol addition occurs primarily following torsional relaxation of the lowest excited singlet states of each isomer, 1 c* and 1 t*, to a common twisted singlet excited state intermediate, 1 p*, initially called the phantom singlet state. The addition is consistent with the zwitterionic character of 1 p*. Ether forms by direct 1,2-addition of CH3OH to the central carbon atoms and by 1,1-addition following rearrangement to 1-benzyl-1-phenylcarbene. Use of CD3OD and GC/MS (gas chromatographic/mass spectroscopic) analysis of the ether products revealed that the ratio of carbene/direct addition pathways is higher starting from cis-stilbene. We conclude that 1 p* formed from 1 c* is hotter than 1 p* formed from 1 t*. Surprisingly, except for favoring the carbene pathway, the use of higher energy photons (254 vs 313 nm) does not affect the overall ether quantum yield starting from cis-stilbene but significantly enhances both pathways starting from trans-stilbene. It appears that carbene formation and direct methanol addition to higher trans-stilbene excited state(s) compete with relaxation to S1. Substitution of D for the vinyl Hs of stilbene enhances the direct addition pathway more than 2-fold and strongly suppresses the carbene insertion pathway, revealing a large, kpcd0/ kped2 = 6.3, primary deuterium isotope effect in the carbene rearrangement. The 2-fold increase in the ether quantum yield is due primarily to a 2.75-fold increase in the lifetime of 1 p* on deuterium substitution of the vinyl hydrogens.

Unusual rearrangement of an N-heterocyclic carbene via a ring-opening and ring-closing process.

The reaction of a pentadentate NHC ligand precursor with Ni(OAc)2·4H2O or Pd(OAc)2 in the presence of a base yields four-coordinate square-planar Ni(ii) and Pd(ii) complexes with an unusual ligand generated in situ. A series of experimental studies point to a ring-opening and ring-closing process via novel C-N bond cleavage and formation.

Normal-to-abnormal rearrangement of an N-heterocyclic carbene with a silylene transition metal complex.

The synthesis and characterization of the N-heterocyclic carbene (NHC) stabilized dichlorosilylene Group 6 metal complexes {(IPr)SiCl2}W(CO)5 (3-W), {(IPr)SiCl2}2Cr(CO)4 (4-Cr), and {(IPr)SiCl2}2W(CO)4 (4-W) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) are reported. Treatment of 3-W with CsOH in the presence of IPr leads to the formation of an abnormal-NHC (aNHC) metal complex (aIPrH)W(CO)5 (6-W) (aIPrH = 1,3-bis(2,6-diisopropylphenyl)imidazol-4-ylidene), unveiling an unprecedented normal-to-abnormal transformation route of an NHC. DFT calculations support the proposed mechanism that involves CsOH mediated deprotonation of the IPr-backbone of 3-W to yield a ditopic carbanionic-NHC (dcNHC) complex 5a-W. Subsequent 1,4-migration of the W(CO)5 moiety and hydrolysis of the unmasked SiCl2 rationalize the formation of 6-W. The desired H2O molecule is generated in the initial step on deprotonation of IPr with CsOH. In contrast to the literature precedents, the calculations indicate that the abnormal complex 6-W is 13.5 kcal mol-1 thermodynamically higher in energy than the normal counterpart (IPr)W(CO)5 (8-W). Interestingly, as the aNHC-compounds reported so far are more stable than their normal counterparts, this finding showcases an opposite trend. Moreover, reaction pathways to the synthesized and related complexes have been investigated by DFT calculations.

Molecular catalysis at polarized interfaces created by ferroelectric BaTiO3.

The local environment at polarized solid-liquid interfaces provides a unique medium for chemical reactions that could be exploited to control the selectivity of non-faradaic reactions. Polarized interfaces are commonly prepared by applying a voltage to an electrode in an electrolyte solution, but it is challenging to achieve high surface charge densities while suppressing faradaic reactions. Ferroelectric materials have permanent surface charge densities that arise from the dipole moments of ferroelectric domains and can be used to create polarized solid-liquid interfaces without applying a voltage. We studied the effects of ferroelectric oxides on the selectivity of a Rh porphyrin-catalyzed carbene rearrangement. The addition of ferroelectric BaTiO3 nanoparticles to the reaction solution changed the product ratio in the same direction and by a similar magnitude as performing the reaction at an electrode-electrolyte interface polarized by a voltage. The results demonstrate that colloidal suspensions of BaTiO3 nanoparticles act as a dispersible polarized interface that can influence the selectivity of non-faradaic reactions.

ChemInform Abstract: Ynol Ethers: Synthesis and Reactivity

AbstractReview: 47 refs.

ChemInform Abstract: Selected Applications of N‐Protected (S)‐2‐(Diazoacetyl)pyrrolidines (Microreview)

AbstractReview: [18 refs.

Selected applications of N-protected (S)-2-(diazoacetyl)pyrrolidines (microreview)

N-Protected (S)-2-(diazoacetyl)pyrrolidines can be considered as a group of the N-protected (S)-proline derivatives. They can be conveniently prepared from the corresponding acyl chloride or mixed anhydride via Arndt–Eistert reaction.1 In recent years, the N-protected (S)-2-(diazoacetyl)-pyrrolidines have been widely explored as easily available, chiral building blocks bearing the reactive diazo function and have found numerous applications for the multistep synthesis of more complicated heterocycles including some natural products and their analogs. Some of them are reported to display biological activities, e.g., antifungal,2 α4β2 nicotinic acetylcholine receptor-binding,3 , 4 oxygen free radical scavenging,5 and selective antihistamine.6 Three types of key reactions performed with N-protected (S)-2-(diazoacetyl)pyrrolidines are a) halogenation via treatment with HX agents and N2 elimination, b) catalytic decomposition and generation of reactive ketenes via the Wolff rearrangement of the intermediate α-oxo carbenes, and c) (3+2) cycloaddition reactions of the diazo 1,3-dipole with C=S dipolarophiles. In this article, mainly the papers from the period after 2001 are reviewed.

Ynol Ethers: Synthesis and Reactivity.

Ynol ethers are highly valuable substrates offering a wide range of reactivity. These highly electron-rich heterosubstitued alkynes can be of great synthetic potential. In this mini-review, the different methods for the synthesis of ynol ethers are first presented, divided in three main approaches involving a β-elimination, a carbene rearrangement and a direct oxidation of an alkyne. Their reactivity is then summarized underlying their synthetic utility. This non-exhaustive review aims at presenting the intrinsic reactivity of these compounds, still underexploited in synthesis.

Studies towards the synthesis of secoiridoids

A new approach to secoiridoids, based on the synthesis of the key functionalized intermediates 4 and 5, is presented. These compounds were tested in formal [3+3] cycloadditions. Acyl-chloride 15 was transformed into enol α,β-unsaturated ester 16, which was involved in a N-heterocyclic carbene rearrangement to give an advanced precursor 17 in the total synthesis of secoiridoids.

An alternative interpretation of the ultracold methylhydroxycarbene rearrangement mechanism: cooperative effects.

Recent studies have reported surprising results related to the rearrangement of carbenes under ultracold conditions, making use of sophisticated models of quantum tunnelling to explain the observed phenomena. Here, we demonstrate that a methylhydroxycarbene (H3C-C-OH) rearrangement is possible by making changes in molecularity (i.e., through cooperative effects), owing to intermolecular hydrogen bond/H-transfer. The model used for accomplishing these changes in molecularity suggests the occurrence of two chemical species during the rearrangement and preferential formation of acetaldehyde. We propose an alternative interpretation for the methylhydroxycarbene rearrangement, as well as for a bimolecular isomerization mechanism for acetaldehyde formation with an activation barrier, Ea, of +0.25 kcal mol(-1), relative to 1a′ (−8.06 kcal mol(-1) relative to 1a); this barrier is lower than that required by H-tunnelling as proposed by Schreiner et al. We also note that the mechanism for obtaining vinyl alcohol leads to the simultaneous formation of acetaldehyde through an Ea of +13.53 kcal mol(-1), relative to 1a (+0.93 kcal mol(-1) relative to 1b), again confirming the predominant presence of acetaldehyde.

Carbene rearrangements in three-coordinate N-heterocyclic carbene complexes of cobalt(II) bis(trimethylsilyl)amide.

The synthesis and molecular structures of the cobalt(II) N-heterocyclic carbene (NHC) complexes [(NHC)Co{N(SiMe3)2}2], where NHC = 1,3-bis(diisopropylphenyl)imidazolylidene (IPr) (6), 1,3-bis(mesityl)imidazolylidene (IMes) (7), and 1,3-bis(tert-butyl)imidazol-2-ylidene (I(t)Bu) (8), are reported. Complexes 6-8 are rare examples of three-coordinate cobalt NHC complexes. The steric congestion within the coordination environments of the cobalt(II) centers in 6 and 7 results in the longest Co-C(NHC) distances currently known. Investigating the thermal stability of 6-8, we have found that the steric congestion in 6 is such that heating the complex to reflux in toluene prompts a rearrangement from the normal, C2-bonding mode of the IPr ligand to the corresponding "abnormal" or mesoionic bonding mode. The rearrangement results in formation of [(aIPr)Co{N(SiMe3)2}2] (9), which is the first cobalt complex of an abnormal NHC ligand. The Co-C bond in 9 is 0.06 Å shorter than the analogous bond in 6, suggesting that, although the rearrangement occurs due to the spatial demands of the IPr ligand, there is also a thermodynamic driving force in terms of the Co-C bond. In contrast to the case for 6, complex 7 is stable with respect to the normal-to-abnormal rearrangement. Refluxing complex 8 in toluene results in activation of a tert-butyl substituent, which is eliminated as isobutene, followed by formation of the 1-tert-butylimidazole complex [((t)BuIm)Co{N(SiMe3)2}2] (10).