The carbon-oxygen bond dissociation enthalpies, BDE(C-O), in several N-alkoxyamine derivatives based on 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) have been determined in the liquid phase by photoacoustic calorimetry. The BDE(C-O) and the BDE(C-H) in the corresponding hydrocarbons follow a linear correlation: BDE(C-O) ) 1.04BDE(C-H) -62.1 kcal mol -1 . When an electronegative element adjacent to the C-O bond is present, as in tetrahydrofuryl, a substantial deviation from the correlation is noticed. Due to the anomeric interaction the (THF) N-alkoxyamine is stabilized by an additional 14 kcal mol -1 . The Arrhenius expression for the homolytic decomposition of methyl-TEMPO in the gas phase obeys k/s -1 ) 10 15.3 exp(-45.3/RT) to yield a BDE(C-O) of 47 ( 1 kcal mol -1 at 298 K. Furthermore, a high reactivity of TEMPO toward hydrogen donors, 1,4-cyclohexadiene or 9,10-dihydroanthracene, has been observed. Above 380 K, TEMPO is converted into the hydroxyamine 2,2,6,6-tetramethyl-1-piperidinol (TEMPOH) and the amine 2,2,6,6tetramethylpiperidine (TEMPH). An acid-catalyzed mechanism for TEMPO deoxygenation is proposed.

The cholesterol-lowering blockbuster drug pravastatin can be produced by stereoselective hydroxylation of the natural product compactin. We report here the metabolic reprogramming of the antibiotics producer Penicillium chrysogenum toward an industrial pravastatin production process. Following the successful introduction of the compactin pathway into the β-lactam-negative P. chrysogenum DS50662, a new cytochrome P450 (P450 or CYP) from Amycolatopsis orientalis (CYP105AS1) was isolated to catalyze the final compactin hydroxylation step. Structural and biochemical characterization of the WT CYP105AS1 reveals that this CYP is an efficient compactin hydroxylase, but that predominant compactin binding modes lead mainly to the ineffective epimer 6-epi-pravastatin. To avoid costly fractionation of the epimer, the enzyme was evolved to invert stereoselectivity, producing the pharmacologically active pravastatin form. Crystal structures of the optimized mutant P450 Prava bound to compactin demonstrate how the selected combination of mutations enhance compactin binding and enable positioning of the substrate for stereo-specific oxidation. Expression of P450 Prava fused to a redox partner in compactin-producing P. chrysogenum yielded more than 6 g/L pravastatin at a pilot production scale, providing an effective new route to industrial scale production of an important drug.pravastatin | P450 engineering | fermentation | statin | cholesterol

The thermal decomposition of gaseous diphenyl ether (DPE) and phenyl vinyl ether (PVE) has been studied, at atmospheric pressure in hydrogen and in a very low-pressure reactor, over a temperature range of 1050−1200 K. The high-pressure rate constant for homolytic bond cleavage C6H5O−C6H5 → C6H5O• + C6H5 • (1) obeys k 1 (s-1) = 1015.50 exp(−75.7/RT). Two pathways can be distinguished for C6H5OC2H3:  C6H5 • + C2H3O• (2) and C6H5O• + C2H3 • (3). The overall rate constant follows k 2+3 (s-1) = 1015.50 exp(−73.3/RT). The rate ratio, v 2/v 3, amounts to 1.8 and appears to be temperature independent. These findings result in bond dissociation energies (BDE) at 298 K for C6H5O−C6H5, C6H5−OC2H3, and C6H5O−C2H3 of 78.8, 75.9, and 76.0 kcal mol-1, respectively. The enthalpies for reactions 1−3 have been also determined at 298 and 1130 K by ab-initio calculations using the density functional theory formalism on the B3LYP/6-31G(d) and B3LYP/6-311++G(d,p) level. Comparison between experiments and theoretical calculations reveals distinct variances (ca. 3−4 kcal mol-1) for the BDE(C−O) in aryl ethers and the BDE(O−H) in phenol and vinyl alcohol but a close agreement for the BDE(C−H) in the related hydrocarbons:  toluene, benzene, and ethene.

The reduction of α‐X‐acetophenones (X = PhO, Br, Cl), as model compounds for lignin liquefaction studies, has been investigated in the presence of a hydrogen‐donating solvent such as 9,10‐dihydroanthracene (AnH2) or 2‐propanol, between 373 and 573 K. With α‐phenoxyacetophenone (PAP) in AnH2, acetophenone and phenol have been obtained with high selectivities. The mechanism involves the reverse radical disproportionation (RRD) with AnH2. Hydrodebromination of α‐bromoacetophenone (BrAP) is quantitative at 423 K using AnH2 as a reducing agent. Now, the hydrogen transfer proceeds by an uninhibited radical chain mechanism with anthracenyl radicals as the chain carriers. For the kinetic analysis, the C–X (X = Br, Cl) bond dissociation enthalpies (BDEs) have been determined by means of very low pressure pyrolysis to give BDE(C–Br) = 271 kJ mol–1 and, as a lower limit, BDE(C–Cl) ≈ 309 kJ mol–1, at 298 K. The BDEs are quite at variance with recently published insights derived from an electrochemical study. For comparison, density functional theory calculations (DFT) have been performed.

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