Acetyl Cyanide Research Articles

Hydrogen Sulfide Chemistry in Continuous Flow: Efficient Synthesis of 2-Oxopropanethioamide

A safe and scalable procedure for the synthesis of 2-oxopropanethioamide, an intermediate in the synthesis of a potent β-secretase (BACE-1) inhibitor, from the reaction of acetyl cyanide with hydrogen sulfide gas under continuous-flow conditions has been developed. The toxic gas could be accurately dosed using a mass-flow controller or a peristaltic pump. The reaction proceeded smoothly at room temperature in the presence of a small amount of triethylamine as basic catalyst. After a residence time of 15 min, excellent yield (96%) and purity (>99%) were obtained for the target compound. The high reaction selectivity permitted a simple workup procedure consisting of evaporation of all volatiles.

Synthesis of fluorescent heterocycles via a Knoevenagel/[4 + 1]-cycloaddition cascade using acetyl cyanide.

A concise one-pot three-component reaction that affords fluorescent indolizines, benzo[d]pyrrolo[2,1-b]thiazoles, and pyrrolo[1,2-a]pyrazines is reported. The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methyl-ene-cyano aza-heterocycles, followed by [4 + 1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement.

ChemInform Abstract: Regioselective Acylation of Diols and Triols: The Cyanide Effect.

Central topics of carbohydrate chemistry embrace structural modifications of carbohydrates and oligosaccharide synthesis. Both require regioselectively protected building blocks that are mainly available via indirect multistep procedures. Hence, direct protection methods targeting a specific hydroxy group are demanded. Dual hydrogen bonding will eventually differentiate between differently positioned hydroxy groups. As cyanide is capable of various kinds of hydrogen bonding and as it is a quite strong sterically nondemanding base, regioselective O-acylations should be possible at low temperatures even at sterically congested positions, thus permitting formation and also isolation of the kinetic product. Indeed, 1,2-cis-diols, having an equatorial and an axial hydroxy group, benzoyl cyanide or acetyl cyanide as an acylating agent, and DMAP as a catalyst yield at −78 °C the thermodynamically unfavorable axial O-acylation product; acyl migration is not observed under these conditions. This phenomenon was sub...

TBD- or PS-TBD-Catalyzed One-Pot Synthesis of Cyanohydrin Carbonates and Cyanohydrin Acetates from Carbonyl Compounds.

Cyanation reactions of carbonyl compounds with methyl cyanoformate or acetyl cyanide catalyzed by 5 mol % of 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) were examined. Using methyl cyanoformate, the corresponding cyanohydrin carbonates were readily obtained in high yield for aromatic and aliphatic aldehydes and ketones. Similar results were obtained when acetyl cyanide was used as the cyanide source. The polymer-supported catalyst, PS-TBD, also acted as a good catalyst for this reaction. PS-TBD was easily recovered and reused with minimal activity loss.

Regioselective Acylation of Diols and Triols: The Cyanide Effect.

Central topics of carbohydrate chemistry embrace structural modifications of carbohydrates and oligosaccharide synthesis. Both require regioselectively protected building blocks that are mainly available via indirect multistep procedures. Hence, direct protection methods targeting a specific hydroxy group are demanded. Dual hydrogen bonding will eventually differentiate between differently positioned hydroxy groups. As cyanide is capable of various kinds of hydrogen bonding and as it is a quite strong sterically nondemanding base, regioselective O-acylations should be possible at low temperatures even at sterically congested positions, thus permitting formation and also isolation of the kinetic product. Indeed, 1,2-cis-diols, having an equatorial and an axial hydroxy group, benzoyl cyanide or acetyl cyanide as an acylating agent, and DMAP as a catalyst yield at -78 °C the thermodynamically unfavorable axial O-acylation product; acyl migration is not observed under these conditions. This phenomenon was substantiated with 3,4-O-unproteced galacto- and fucopyranosides and 2,3-O-unprotected mannopyranosides. Even for 3,4,6-O-unprotected galactopyranosides as triols, axial 4-O-acylation is appreciably faster than O-acylation of the primary 6-hydroxy group. The importance of hydrogen bonding for this unusual regioselectivity could be confirmed by NMR studies and DFT calculations, which indicate favorable hydrogen bonding of cyanide to the most acidic axial hydroxy group supported by hydrogen bonding of the equatorial hydroxy group to the axial oxygen. Thus, the "cyanide effect" is due to dual hydrogen bonding of the axial hydroxy group which enhances the nucleophilicity of the respective oxygen atom, permitting an even faster reaction for diols than for mono-ols. In contrast, fluoride as a counterion favors dual hydrogen bonding to both hydroxy groups leading to equatorial O-acylation.

ChemInform Abstract: Regulation of Nonadiabatic Processes in the Photolysis of Some Carbonyl Compounds

AbstractReview: 83 refs.

Regulation of nonadiabatic processes in the photolysis of some carbonyl compounds.

Carbonyl compounds studied are confined to acetyl halide (CH3COCl), acetyl cyanide (CH3COCN), acetyl sulfide (CH3COSH), acetaldehyde (CH3CHO), and methyl formate (HCOOCH3). They are asymmetrically substituted, but do not follow the well-known Norrish type I reactions. Each compound ejected in an effusive beam at about 300 K is commonly excited to the (1)(n, π*)CO lower state; that is, a nonbonding electron on O of the C[double bond, length as m-dash]O group is promoted to the antibonding orbital of π*CO. The photolysis experiments are conducted in the presence of Ar gas and the corresponding fragments are detected using time-resolved Fourier-transform Infrared (FTIR) emission spectroscopy. The enhancement of the collision-induced internal conversion or intersystem crossing facilitates the dissociation channels via highly vibrational states of the ground singlet (So) or triplet (T1) potential energy surfaces. In this manner, an alternative nonadiabatic channel is likely to open yielding different products, even if the diabatic coupling strength is strong between the excited state and the neighboring state. For instance, the photodissociation of CH3COCl at 248 nm produces HCl, CO, and CH2 fragments, in contrast to the supersonic jet experiments showing dominance of the Cl fragment eliminated from the excited state. If the diabatic coupling strength is weak, dissociation proceeds mainly through internal conversion, such as the cases of CH3COCN and CH3COSH. The photodissociation of CH3COCN at 308 nm has never been reported before, while for CH3COSH matrix-isolated photodissociation was conducted that shows a distinct spectral feature from the current FTIR method. The CH3CHO and HCOOCH3 molecules belong to the same type of carbonyl compounds, in which the molecular products, CO + CH4 and CO + CH3OH, are produced through both transition state and roaming pathways. Their products are characterized differently between molecular beam and current FTIR experiments. For instance, the photodissociation of HCOOCH3 at 248 nm yields CO with the vibrational state v ≥ 4, in contrast to the molecular beam experiments producing CO at v = 1. The photodissociation of CH3CHO at 308 nm intensifies a low energy component in the CH4 vibrational distribution, thus verifying the transition state pathway for the first time.

Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study.

A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

Accurate structural and spectroscopic characterization of prebiotic molecules: The neutral and cationic acetyl cyanide and their related species.

In an effort to provide an accurate structural and spectroscopic characterization of acetyl cyanide, its two enolic isomers and the corresponding cationic species, state-of-the-art computational methods, and approaches have been employed. The coupled-cluster theory including single and double excitations together with a perturbative treatment of triples has been used as starting point in composite schemes accounting for extrapolation to the complete basis-set limit as well as core-valence correlation effects to determine highly accurate molecular structures, fundamental vibrational frequencies, and rotational parameters. The available experimental data for acetyl cyanide allowed us to assess the reliability of our computations: structural, energetic, and spectroscopic properties have been obtained with an overall accuracy of about, or better than, 0.001 Å, 2 kcal/mol, 1-10 MHz, and 11 cm(-1) for bond distances, adiabatic ionization potentials, rotational constants, and fundamental vibrational frequencies, respectively. We are therefore confident that the highly accurate spectroscopic data provided herein can be useful for guiding future experimental investigations and/or astronomical observations.

N‐Heterocyclic Carbene‐Catalysed Direct Synthesis of Cyano Esters via Cyanation‐Esterification Reaction of α‐Keto Esters

AbstractThe cyanation‐esterification reaction of α‐keto esters catalysed by N‐heterocyclic carbenes (NHCs) is developed. Under the catalysis of 10 mol% 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene, aromatic and aliphatic α‐keto esters reacted with ethyl cyanoformate or acetyl cyanide to produce the corresponding cyano esters with a tetrasubstituted carbon center in high yields.

Acetyl cyanide as a cyanide source in a tandem catalyst-free modified Groebke–Blackburn–Bienaymé [4+1]-cycloaddition-Strecker cascade

A concise one-pot 3-step cascade reaction to biologically significant imidazo[1,2-a]heterocycles is described. The methodology utilizes acetyl cyanide as a non-classical isocyanide replacement for TMSCN in a microwave-assisted [4+1] cycloaddition (the Groebke–Bienaymé–Blackburn reaction) followed by a Strecker reaction under catalysis free conditions. The methodology proceeds with operational simplicity, short reaction times, and high bond forming efficiency.

VUV photoionization and dissociative photoionization of the prebiotic molecule acetyl cyanide: theory and experiment.

The present combined theoretical and experimental investigation concerns the single photoionization of gas-phase acetyl cyanide and the fragmentation pathways of the resulting cation. Acetyl cyanide (AC) is inspired from both the chemistry of cyanoacetylene and the Strecker reaction which are thought to be at the origin of medium sized prebiotic molecules in the interstellar medium. AC can be formed by reaction from cyanoacetylene and water but also from acetaldehyde and HCN or the corresponding radicals. In view of the interpretation of vacuum ultraviolet (VUV) experimental data obtained using synchrotron radiation, we explored the ground potential energy surface (PES) of acetyl cyanide and of its cation using standard and recently implemented explicitly correlated methodologies. Our PES covers the regions of tautomerism (between keto and enol forms) and of the lowest fragmentation channels. This allowed us to deduce accurate thermochemical data for this astrobiologically relevant molecule. Unimolecular decomposition of the AC cation turns out to be very complex. The implications for the evolution of prebiotic molecules under VUV irradiation are discussed.

Note: Photodissociation of CH3COCN at 308 nm by time-resolved Fourier-transform infrared emission spectroscopy: Is CO a primary or secondary product?

This Note aims to clarify the source of CO in photodissociation of acetyl cyanide (CH3COCN) at 308 nm. From the theoretical aspects, a new pathway via isomerization transition state (TS) at 391 ± 8 kJ∕mol is found leading to the CO + CH3NC products. An amount of 60% reactant molecules at 300 K is estimated to successfully surpass the average TS barrier lying above the excitation energy by 3.5 kJ∕mol. Further, a prior distribution method is conducted to characterize the vibrational energy distribution of CO on a statistical basis. The pathway to CH3NC + CO yields a vibrational branching ratio (v = 0:v = 1:v = 2:v = 3∼0.63:0.25:0.093:0.032) in excellent agreement with the observation (0.62:0.25:0.09:0.05).

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed Cyanation Reaction of Carbonyl Compounds with Ethyl Cyanoformate and Acetyl Cyanide.

Abstract N-heterocyclic carbene (NHC) has been employed as an efficient catalyst for cyanation reaction of carbonyl compounds. Under catalysis of 1 mol % NHCs, various aldehydes and 2,2,2-trifluoroacetophenone coupled with ethyl cyanoformate in THF to provide cyanohydrins ethyl carbonates in excellent yields. While in the presence of 10 mol % catalyst, different types of aldehydes and 2,2,2-trifluoroacetophenone reacted with acetyl cyanide in dichloroethane to give acylated cyanohydrins in moderate to high yields.

Gas-phase photodissociation of CH3COCN at 308 nm by time-resolved Fourier-transform infrared emission spectroscopy

By using time-resolved Fourier-transform infrared emission spectroscopy, the fragments of HCN(v = 1, 2) and CO(v = 1-3) are detected in one-photon dissociation of acetyl cyanide (CH(3)COCN) at 308 nm. The S(1)(A(")), (1)(n(O), π(∗) (CO)) state at 308 nm has a radiative lifetime of 0.46 ± 0.01 μs, long enough to allow for Ar collisions that induce internal conversion and enhance the fragment yields. The rate constant of Ar collision-induced internal conversion is estimated to be (1-7) × 10(-12) cm(3) molecule(-1) s(-1). The measurements of O(2) dependence exclude the production possibility of these fragments via intersystem crossing. The high-resolution spectra of HCN and CO are analyzed to determine the ro-vibrational energy deposition of 81 ± 7 and 32 ± 3 kJ∕mol, respectively. With the aid of ab initio calculations, a two-body dissociation on the energetic ground state is favored leading to HCN + CH(2)CO, in which the CH(2)CO moiety may further undergo secondary dissociation to release CO. The production of CO(2) in the reaction with O(2) confirms existence of CH(2) and a secondary reaction product of CO. The HNC fragment is identified but cannot be assigned, as restricted to a poor signal-to-noise ratio. Because of insufficient excitation energy at 308 nm, the CN and CH(3) fragments that dominate the dissociation products at 193 nm are not detected.

N-heterocyclic carbene catalyzed cyanation reaction of carbonyl compounds with ethyl cyanoformate and acetyl cyanide

N-heterocyclic carbene (NHC) has been employed as an efficient catalyst for cyanation reaction of carbonyl compounds. Under catalysis of 1mol% NHCs, various aldehydes and 2,2,2-trifluoroacetophenone coupled with ethyl cyanoformate in THF to provide cyanohydrins ethyl carbonates in excellent yields. While in the presence of 10mol% catalyst, different types of aldehydes and 2,2,2-trifluoroacetophenone reacted with acetyl cyanide in dichloroethane to give acylated cyanohydrins in moderate to high yields.

Opposite Enantiomers from Minor Enantiomer Recycling and Dynamic Kinetic Resolution Using a Single Biocatalyst

AbstractA one‐pot recycling procedure comprising Lewis acid catalyzed enantioselective addition of acetyl cyanide to (E)‐2‐butenal to give the O‐acetylated cyanohydrin and enzyme‐catalyzed conversion of the minor product enantiomer back to (E)‐2‐butenal provided essentially enantiopure (2R,3E)‐2‐acetoxy‐3‐pentenenitrile in close to quantitative yield. The opposite enantiomer was obtained, albeit in lower yield and with lower enantiomeric purity than that observed from the minor enantiomer recycling, by dynamic kinetic resolution consisting of reversible addition of HCN to the aldehyde coupled to enzyme‐catalyzed acetylation of the cyanohydrin.

Analysis of the rotational spectrum of pyruvonitrile up to 324 GHz

The room-temperature rotational spectrum of pyruvonitrile (acetyl cyanide, CH 3COCN) was measured up to 324 GHz, and additional measurements were also made in supersonic expansion in the region 7–19 GHz. The available data sets for the A and E torsional sublevels were extended to over 1200 transitions, J = 65 and K a = 38 for the ground vibrational state, and to comparable numbers of transitions for first excited states of the methyl torsional mode ν 18, and the in-plane CCN bending mode ν 12. The collected experimental measurements were fitted with several different computer programs for dealing with the effects of methyl torsional motion on the rotational spectrum and many spectroscopic constants have been determined. The experimental results are discussed in detail and are augmented by ab initio computations. Stark effect measurements in supersonic expansion were used to precisely determine the electric dipole moment of pyruvonitrile, ∣ μ a ∣ = 2.462(2) D, ∣ μ b ∣ = 2.442(2) D, μ tot = 3.468(2) D. Pyruvonitrile, as an 8-atom molecule with a sizable dipole moment, is a possible candidate for astrophysical detection and the present work provides the laboratory data necessary for that purpose.

Lewis base-catalyzed three-component Strecker reaction on water. An efficient manifold for the direct α-cyanoamination of ketones and aldehydes

The first three-component organocatalyzed Strecker reaction operating on water has been developed. The manifold utilizes ketones (aldehydes) as the starting carbonyl component, aniline as the primary amine, acetyl cyanide as the cyanide source and N,N-dimethylcyclohexylamine as the catalyst.

The Catalytic Acylcyanation of Imines

The catalytic acylcyanation of aldimines with acylcyanides and a direct three-component variant involving the generation of an imine in situ have been developed. Furthermore, a highly enantioselective version has been established, culminating in the first organocatalytic asymmetric three-component Strecker reaction. Jacobsen thiourea catalysts were found to catalyze the reaction with excellent enantioselectivities, whereas binol phosphates (binol = 1,1'-bi-2,2'-naphthol) proved to be catalytically active but only modestly enantioselective. A large number of different substrates could be used in the processes described, thus illustrating the potential of our reaction for the generation of diversity within the attractive alpha-amino carbonyl framework. Furthermore, a novel cyclic amidine was obtained from the reaction of acetyl cyanide with ketimines.