Cyclohexane Carboxaldehyde Research Articles

Hydrogen by Deuterium Substitution in an Aldehyde Tunes the Regioselectivity by a Nonheme Manganese(III)-Peroxo Complex.

Mononuclear nonheme MnIII -peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side-on MnIII -peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C-H by C-D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy.

Hydrogen by Deuterium Substitution in an Aldehyde Tunes the Regioselectivity by a Nonheme Manganese(III)–Peroxo Complex

AbstractMononuclear nonheme MnIII‐peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side‐on MnIII‐peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C−H by C−D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy.

Mechanistic Investigation of the Reactions between Cyclohexane Carboxaldehyde and Ureido Groups

Model reactions have been performed to explore the reactivity of a variety of ureido groups with cyclohexane carboxaldehyde. The reaction mechanism between ureido and aldehyde functionalities is more complicated than expected. A new heterocyclic product was identified, which is very stable and solvent resistant. The final product profile is reactant and solvent dependent. In the cases of urea, alkyl urea, and benzyl urea, the reaction pathway goes from hemiaminal to aminal, to enamine, and finally to the heterocyclic product with nearly 100% yield. For other investigated ureido groups, the reaction stopped at the enamine product, and products are a mixture of hemiaminal, aminal, and enamine. All reaction steps are reversible except for the last step. The structure of the unique cyclic product was determined combining NMR and LC–MS analysis, and the reaction pathway was verified by kinetics studies.

Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α-methylbenzyl amine for cis-aziridines from α-diazo esters and for trans-aziridines from α-diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis-aziridines involved the (R)-amine with the (S)-ligand, but curiously, for trans-aziridines the matched case involved the (R)-amine with the (R)-ligand for imines derived from benzaldehyde and n-butanal, and the (R)-amine with the (S)-ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.

Intramolecular “Hydroiminiumation” of Alkenes: Application to the Synthesis of Conjugate Acids of Cyclic Alkyl Amino Carbenes (CAACs).

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Phosphonate Modification for a Highly (Z)‐Selective Synthesis of Unsaturated Esters by Horner–Wadsworth–Emmons Olefination

AbstractThe Horner–Wadsworth–Emmons (HWE) reaction of various ethyl diarylphosphonoacetates with benzaldehyde, cyclohexane carboxaldehyde and octanal is reported. Selectivities of up to 98 % at –78 °C are obtained with the three substrates. Among all the phosphonates prepared, the reagent based on 2‐tert‐butylphenol proved to be especially efficient, with Z/E ratios close to 95:5 at 0 °C. It appears thus to be the reagent of choice for the (Z)‐selective HWE reaction with both aromatic and aliphatic aldehydes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

{RhCl(CO)2}2]-Derived MCM-41-Tethered Rhodium Complex Catalysts via Phosphine, Amine and Thiol Ligands for Cyclohexene Hydroformylation

Abstract Functionalized silicate MCM-41-tethered rhodium complexes derived from [{RhCl(CO)2}2] have been studied by infrared spectroscopy (IR), X-ray diffraction (XRD) and N2 adsorption–desorption. [{RhCl(CO)2}2] reacts with aminated MCM-41 to result in a splitting of the chloride bridge. The same result is presumed with phosphinated MCM-41. Thiolated MCM-41 is presumed to displace the chloride in the bridge with thiol ligands. The tethering of rhodium complexes to MCM-41 leads to reduced pore sizes, pore volumes and BET surface areas without altering the structural ordering of MCM-41. The MCM-41-tethered catalysts show distinct activities and resistance to rhodium leaching in cyclohexene hydroformylation under equimolar CO and H2 at 28 bar and 100 °C, depending on the nature of complexation of the supported donor ligands with the rhodium centre. The aminated MCM-41-tethered catalyst displays good activity, selectivity and recycling for the formation of cyclohexane carboxaldehyde. The mesoporous structure of MCM-41 remains stable during the reaction.

Theoretical vibrational spectra of organic ring compounds compared to experiment

AbstractWe have studied vibrational infrared (IR) and Raman spectra of several organic ring compounds. These include first cyclobutanecarboxaldehyde (CBA) and cyclohexanecarboxaldehyde (CHA) using density functional theory (DFT) together with a Becke‐3 exchange and Lee–Yang–Parr correlation (B3LYP) functional. DFT in these systems gives a stable and low‐energy gauche‐axial (g‐ax) conformer for both of the molecules together with the experimentally found equatorial conformations. However, on the basis of comparison of the theoretical vibrational spectra of the conformational mixture at 300 K with experimental spectra, the presence of the g‐ax conformer could be ruled out because it would yield extra lines not present in the corresponding experimental spectra. Thus, we concluded that DFT yields properties related to energy derivatives such as minimum geometries and vibrational spectra in fair agreement with experiment, while total energy differencies are not trustworthy when they are small, especially if small linear dependencies in the atomic basis sets applied appear. However, in that case we found that Møller–Plesset perturbation theory of second order (MP2) applied to CBA has the same problems and even does not predict the absolute minimum on the potential hypersurface correctly. Therefore, we applied DFT also to biphenyle (BP) and terphenyle (TP). Again, in BP and TP DFT turned out to yield reliable structures that as far as the important torsional angle between the rings is concerned are even better than MP2. Also, the vibrational spectra are in fair agreement with experimental ones. In BP restricted Hartree–Fock (RHF), DFT and experimental IR spectra all show two intense absorptions around 700 cm−1, while MP2 gives only one intense absorption band in this region. DFT also reproduces the position of these two lines well. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2004

Rh4(CO)12-derived functionalized MCM-41-tethered rhodium complexes: preparation, characterization and catalysis for cyclohexene hydroformylation

Abstract The preparation of Rh 4 (CO) 12 -derived functionalized silicate MCM-41-tethered catalysts has been studied by infrared (IR) spectroscopy, X-ray diffraction (XRD) and N 2 adsorption–desorption. Silicate MCM-41 is first functionalized with phosphine, amine and thiol donor ligand groups. Then the functionalized MCM-41 is reacted with Rh 4 (CO) 12 by coordination of surface donor ligands to the rhodium to produce phosphinated and aminated MCM-41-tethered unidentified rhodium carbonyl clusters and MCM-41-tethered [Rh(μ-S(CH 2 ) 3 Si(O s ) 3 )(CO) 2 ] 2 (where O s represents surface oxygen). The functionalized MCM-41 and Rh/functionalized MCM-41 possess the structural ordering of mesoporous MCM-41, but exhibit reduced pore sizes, total pore volumes and BET surface areas. The tethered rhodium carbonyl catalysts behave differently with different donor ligands attached in cyclohexene hydroformylation under equimolar CO and H 2 at 2.7 MPa and 100 °C. Only the aminated MCM-41-tethered catalyst displays good activity, selectivity and recycling for the formation of cyclohexane carboxaldehyde. The influences of supported donor ligands on the activity and stability of tethered catalysts for hydroformylation are discussed. The mesoporous structure of MCM-41 is maintained stable during the catalytic reaction.

Consequences of correlated solvation on the structures and reactivities of RLi-diamine complexes: 1,2-addition and alpha-lithiation reactions of imines by TMEDA-solvated n-butyllithium and phenyllithium.

6Li and (13)C NMR spectroscopic studies were carried out on [(6)Li]n-BuLi and [(6)Li]PhLi (RLi) in toluene-d(8) containing the following diamines: N,N,N',N'-tetramethylethylenediamine (TMEDA), N,N,N',N'-tetraethylethylenediamine, 1,2-dipyrrolidinoethane, 1,2-dipiperidinoethane, N,N,N',N'-tetramethylpropanediamine, trans-(R,R)-N,N,N',N'-tetramethylcyclohexanediamine, and (-)-sparteine. Dimers of general structure (RLi)(2)S(2) (S = chelating diamine) are formed in each case. Treatment of RLi with two different diamines (S and S') affords homosolvates (RLi)(2)S(2) and (RLi)(2)S'(2) along with a heterosolvate (RLi)(2)SS'. Relative binding constants and associated free energies for the sequential solvent substitutions are obtained by competing pairs of diamines. The high relative stabilities of certain heterosolvates indicate that solvent binding to the RLi dimer can be highly correlated. Rate studies of both the 1,2-addition of RLi/TMEDA to the N-isopropylimine of cyclohexane carboxaldehyde and the RLi/TMEDA-mediated alpha-lithiation of the N-isopropylimine of cyclohexanone reveal monomer-based transition structures, [(RLi)(TMEDA)(imine)], in all cases. The complex relationships of solvent binding constants and relative reactivities toward 1,2-additions and alpha-lithiations are discussed.

Catalyst structural effects in titanocene-catalyzed pinacol coupling: activity, stereoselectivity and mechanistic implications

The effects of catalyst structural variation on the activity and selectivity of titanocene-catalyzed pinacol coupling of cyclohexane carboxaldehyde by Mn/TMSCl have been evaluated. Complexes which have been tested include: Cp 2TiCl 2 ( 1), Cp 2TiBr 2 ( 2), (C 5Me 5) 2TiCl 2 ( 3), (1,3- t-Bu 2C 5H 3) 2TiCl 2 ( 4), (1,3- t-Bu 2C 5H 3)(Cp)TiCl 2 ( 5), ansa-[(η 5-tetrahydroindenyl)CH 2CH 2(η 5-tetrahydroindenyl)]TiCl 2 ( 6), and ansa-[(η 5-Cp)CH 2CH 2(η 5-fluorenyl)]TiCl 2 ( 7). Cp 2TiCl 2 ( 1) is the most active (pre)catalyst for pinacol silylether ( 8a) formation, but Brintzinger's complex 6 provides the best dl /meso diastereoselectivity (5:1). Complexes 2, 4 and 7 slowly catalyze the predominant formation of the corresponding pinacol acetal 9a as a secondary product. Comparative stoichiometric reactions of benzaldehyde/Me 3SiCl with [Cp 2TiCl·MnCl 2(THF) 2·Cp 2TiCl] ( 10) and [Cp 2TiCl] 2 ( 11) result in highly diastereoselective pinacol silylether formation with binuclear 11 (29:1), but primarily the production of pinacol acetal ( 9b) from trimetallic 10, suggesting a dominant role for the binuclear complex (or derived mononuclear species) in the catalytic systems employing Cp 2TiCl 2/M/TMSCl, contrary to previous suggestions.

Interaction of human aldehyde dehydrogenase with aromatic substrates and ligands

The substrate benzaldehyde (but not propionaldehyde) could elute aldehyde dehydrogenase from a p-hydroxyacetophenone-affinity column, and inhibit the esterase activity ( K i=47 μM), indicating that this simple aromatic aldehyde binds to the free enzyme and possibly in the substrate-binding site. Thus, the kinetic mechanism for aldehyde dehydrogenase might be dependent upon which aldehyde is used in the reaction. Chloramphenicol which also elutes the enzyme from the affinity column, shows a discriminatory effect by inhibiting the ALDH1 oxidation of benzaldehyde and activating that of propionaldehyde while showing no effect when assayed with hexanal or cyclohexane–carboxaldehyde. Chloramphenicol is an uncompetitive inhibitor against NAD when benzaldehyde is the substrate. We propose that this drug might interact with both the benzaldehyde and NAD binding sites.

BF3-Mediated Addition of Lithium Phenylacetylide to an Imine: Correlations of Structures and Reactivities. BF3·R3N Derivatives as Substitutes for BF3·Et2O

BF3-mediated additions of lithium phenylacetylide (PhCCLi) to the N-(n-butyl)imine of cyclohexane carboxaldehyde were investigated. IR spectroscopic investigations reveal dramatic aging effects on ...

Airborne Aldehydes from Heating Rosin Core Solder and Liquid Rosin Flux to Soldering Temperatures

Gas phase aldehydes produced from heating rosin core solder and liquid rosin flux to temperatures commonly used in soldering were trapped on sampling tubes containing XAD-2 resin coated with the derivatizing agent 2-hydroxymethylpiperidine. Analysis of the resulting oxazolidine derivatives was performed using gas chromatography/mass spectrometry (GC/MS). The observed aldehyde derivatives included formaldehyde, acetaldehyde, propionaldehyde, acrolein, isobutyraldehyde, butyraldehyde, isovaleraldehyde, valeraldehyde, furfural, hexanal, cyclohexane carboxaldehyde and other unidentified compounds likely to be aldehyde isomers. Formaldehyde, acetaldehyde, and benzaldehyde were detected in blank samples. By comparison with an internal standard, a sample produced by drawing air with contaminants derived by heating rosin core solder through a sampling tube contained levels of formaldehyde and acetaldehyde much greater than seen in sampling tube blanks. Benzaldehyde was not shown to be present at a significantly greater level in samples from heating rosin core solder than in blanks prepared using the same analysis protocol. The use of National Institute of Occupational Safety and Health (NIOSH) method 2539 extraction procedures produced blanks with levels of formaldehyde significantly lower than with a modified extraction method (methylene chloride, no sonication). The modified extraction method produced significantly lower benzaldehyde levels in blanks compared with the NIOSH extraction method using toluene and sonication of sampling sorbent tubes.

Airborne Aldehydes from Heating Rosin Core Solder and Liquid Rosin Flux to Soldering Temperatures

Gas phase aldehydes produced from heating rosin core solder and liquid rosin flux to temperatures commonly used in soldering were trapped on sampling tubes containing XAD-2 resin coated with the derivatizing agent 2-hydroxymethylpiperidine. Analysis of the resulting oxazolidine derivatives was performed using gas chromatography/mass spectrometry (GC/MS). The observed aldehyde derivatives included formaldehyde, acetaldehyde, propionaldehyde, acrolein, isobutyraldehyde, butyraldehyde, isovaleraldehyde, valeraldehyde, furfural, hexanal, cyclohexane carboxaldehyde and other unidentified compounds likely to be aldehyde isomers. Formaldehyde, acetaldehyde, and benzaldehyde were detected in blank samples. By comparison with an internal standard, a sample produced by drawing air with contaminants derived by heating rosin core solder through a sampling tube contained levels of formaldehyde and acetaldehyde much greater than seen in sampling tube blanks. Benzaldehyde was not shown to be present at a significantly greater level in samples from heating rosin core solder than in blanks prepared using the same analysis protocol. The use of National Institute of Occupational Safety and Health (NIOSH) method 2539 extraction procedures produced blanks with levels of formaldehyde significantly lower than with a modified extraction method (methylene chloride, no sonication). The modified extraction method produced significantly lower benzaldehyde levels in blanks compared with the NIOSH extraction method using toluene and sonication of sampling sorbent tubes.

Trans-1,3-dithiane-1,3-dioxide; a chiral acyl anion equivalent. Enantioselective synthesis of α-hydroxy- carboxylic acids, esters, amides and ketones

The reaction of ( R, R)-(+)-1,3-dithiane-1,3-dioxide with aldehydes has been carried out and the dithiane dioxide moiety elaborated further. ( R, R)-(+)-1,3-Dithiane-1,3-dioxide gave highly diastereoselective addition products with benzaldehyde and 3,4-dimethoxybenzaldehyde and single diastereomers were isolated in 84 and 76% purified yields respectively. Under similar conditions cyclohexane carboxaldehyde gave an easily separable mixture of diastereomers in 86% total isolated yield. The adducts were transformed into protected S-ethyl α-hydroxythioesters in 95–100% ee via a Pummerer reaction and subsequent trans-thioesterification protocol using LiSEt. Using LiSEt little racemisation occurred even with aryl substituted thioesters. Further transformations of thioesters to various α-hydroxy carboxylic acid derivatives (acids, esters, amides) without racemisation have been achieved. The approach resulted in the synthesis of the dimethyl ether of ( R)-(−)-3,4-dihydroxymandelic acid in its naturally occurring form. Addition of dibutyl cuprate (derived from BuMgBr and Cu(I)Br) to the thioester gave the corresponding ketone in high yield and again without racemisation.

Peroxo-iron and oxenoid-iron species as alternative oxygenating agents in cytochrome P450-catalyzed reactions: switching by threonine-302 to alanine mutagenesis of cytochrome P450 2B4.

Among biological catalysts, cytochrome P450 is unmatched in its multiplicity of isoforms, inducers, substrates, and types of chemical reactions catalyzed. In the present study, evidence is given that this versatility extends to the nature of the active oxidant. Although mechanistic evidence from several laboratories points to a hypervalent iron-oxenoid species in P450-catalyzed oxygenation reactions, Akhtar and colleagues [Akhtar, M., Calder, M. R., Corina, D. L. & Wright, J. N. (1982) Biochem. J. 201, 569-580] proposed that in steroid deformylation effected by P450 aromatase an iron-peroxo species is involved. We have shown more recently that purified liver microsomal P450 cytochromes, including phenobarbital-induced P450 2B4, catalyze the analogous deformylation of a series of xenobiotic aldehydes with olefin formation. The investigation presented here on the effect of site-directed mutagenesis of threonine-302 to alanine on the activities of recombinant P450 2B4 with N-terminal amino acids 2-27 deleted [2B4 (delta2-27)] makes use of evidence from other laboratories that the corresponding mutation in bacterial P450s interferes with the activation of dioxygen to the oxenoid species by blocking proton delivery to the active site. The rates of NADPH oxidation, hydrogen peroxide production, and product formation from four substrates, including formaldehyde from benzphetamine N-demethylation, acetophenone from 1-phenylethanol oxidation, cyclohexanol from cyclohexane hydroxylation, and cyclohexene from cyclohexane carboxaldehyde deformylation, were determined with P450s 2B4, 2B4 (delta2-27), and 2B4 (delta2-27) T302A. Replacement of the threonine residue in the truncated cytochrome gave a 1.6- to 2.5-fold increase in peroxide formation in the presence of a substrate, but resulted in decreased product formation from benzphetamine (9-fold), cyclohexane (4-fold), and 1-phenylethanol (2-fold). In sharp contrast, the deformylation of cyclohexane carboxaldehyde by the T302A mutant was increased about 10-fold. On the basis of these findings and our previous evidence that aldehyde deformylation is supported by added H202, but not by artificial oxidants, we conclude that the iron-peroxy species is the direct oxygen donor. It remains to be established which of the many other oxidative reactions involving P450 utilize this species and the extent to which peroxo-iron and oxenoid-iron function as alternative oxygenating agents with the numerous isoforms of this versatile catalyst.

Catalysis by cytochrome P-450 of an oxidative reaction in xenobiotic aldehyde metabolism: deformylation with olefin formation.

As we have briefly described elsewhere, cytochrome P-450 catalyzes the oxidative deformylation of cyclohexane carboxaldehyde to yield cyclohexene and formic acid in a reaction believed to involve a peroxyhemiacetal-like adduct formed between the substrate and molecular oxygen-derived hydrogen peroxide. This reaction is a useful model for the demethylation reactions catalyzed by the steroidogenic P-450s, aromatase, and lanosterol demethylase. In the present study, the cytochrome P-450-catalyzed formation of olefinic products from a series of xenobiotic aldehydes has been demonstrated. Isobutyraldehyde and trimethylacetaldehyde, but not propionaldehyde, are converted to the predicted olefinic products, suggesting a requirement for branching at the alpha carbon. In addition, the four C5 aldehydes of similar hydrophobicity were compared for their ability to undergo the reaction. The straight-chain valeraldehyde gave no olefinic products with five different rabbit liver microsomal P-450 isozymes. However, increasing activity was seen with the other isomers in the order of isovaleraldehyde, 2-methylbutyraldehyde, and trimethylacetaldehyde, with all of the P-450 cytochromes. The catalytic rate with trimethylacetaldehyde is highest with antibiotic-inducible P-450 form 3A6, followed by phenobarbital-inducible form 2B4 and ethanol-inducible form 2E1. Citronellal, a beta-branched aldehyde that is found in many essential oils and is widely used as an odorant and a flavorant, was found to undergo the oxidative deformylation reaction to yield 2,6-dimethyl-1,5-heptadiene, but only with P-450 2B4. The oxidative cleavage reaction with olefin formation appears to be widespread, as judged by the variety of aldehydes that serve as substrates and of P-450 cytochromes that serve as catalysts.

A pathway to 3-(β-D-ribofuranosyl)-4-nitro-5-ethoxycarbonyl-isoxazoles, useful in the synthesis of pyrazofurin analogues

The synthesis of 3-cyclohexyl and 3-β-D-ribofuranosyl-4-nitro-5-ethoxycarbonyl isoxazole, is realized by conversion of cyclohexane carboxaldehyde and 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allose into the corresponding nitromethyloximes followed by reaction with ethylchlorooxoacetate.