Para-substituted Benzoic Acids Research Articles

Ligand Promoted Pd-Catalyzed High para-Selective C-H Olefination.

Achieving high para-selective C-H functionalized products of benzoic acid derivatives using a designed template is still a daunting challenge because the carbonyl group also could coordinate with metal to activate the ortho-C-H bond. Herein, we report the ligand promoted high para-selective C-H olefination of benzoic acid derivatives; we screened a series of ligands increasing the ratio of p:others from 62:38 to 96:4. This work may find application in the construction of para-substituted benzoic acid derivatives.

Alkylbenzoic and Alkyloxybenzoic Acid Blending for Expanding the Liquid Crystalline State and Improving Its Rheology.

Thermotropic mesogens typically exist as liquid crystals (LCs) in a narrow region of high temperatures, making lowering their melting point with the temperature expansion of the mesophase state an urgent task. Para-substituted benzoic acids can form LCs through noncovalent dimerization into homodimers via hydrogen bonds, whose strength and, consequently, the temperature region of the mesophase state can be potentially altered by creating asymmetric heterodimers from different acids. This work investigates equimolar blends of p-n-alkylbenzoic (kBA, where k is the number of carbon atoms in the alkyl radical) and p-n-alkyloxybenzoic (kOBA) acids by calorimetry and viscometry to establish their phase transitions and regions of mesophase existence. Non-symmetric dimerization of acids leads to the extension of the nematic state region towards low temperatures and the appearance of new monotropic and enantiotropic phase transitions in several cases. Moreover, the crystal-nematic and nematic-isotropic phase changes have a two-step character for some acid blends, suggesting the formation of symmetric and asymmetric associates from heterodimers. The mixing of 6BA and 8OBA most strongly extends the region of the nematic state towards low temperatures (from 95-114 °C and 108-147 °C for initial homodimers, respectively, to 57-133 °C for the resulting heterodimer), whereas the combination of 4OBA and 5OBA gives the most extended high-temperature nematic phase (up to 156 °C) and that of 6BA and 9OBA (or 12OBA) provides the existence of a smectic phase at the lowest temperatures (down to 51 °C).

Structure determination through powder X-ray diffraction, Hirshfeld surface analysis, and DFT studies of 2- and 4-(methylthio)benzoic acid

Abstract 2-(methylthio)benzoic acid (1) is an ortho-substituted benzoic acid derivative, whereas 4-(methylthio)benzoic acid (2) is a para-substituted benzoic acid derivative. The structural analysis of both compounds was carried out using PXRD data. 2-(methylthio)benzoic acid shows a triclinic system with the P 1 ‾ $P\overline{1}$ space group, whereas 4-(methylthio)benzoic acid shows a monoclinic system and crystallizes in the P21/a space group. The strength, as well as relative contributions of intermolecular hydrogen bonds, have been examined through Hirshfeld surfaces as well as 2D fingerprint plots. A weak intramolecular hydrogen bond was found only in the case of ortho-substituted 2-(methylthio)benzoic acid. Supramolecular frameworks for 1 are formed by the interplay of intramolecular and intermolecular interactions, whereas for 2, intermolecular contacts form supramolecular assemblies. Intermolecular O–H⋯O interactions involving carboxyl groups form the R2 2(8) graph-set motif for both compounds. Theoretical DFT calculations using the B3LYP correlation functional reveal that the energy gap of HOMO–LUMO orbitals in compound 1, with the methylthio moiety in the ortho position relative to the carboxyl group, is lower than that of compound 2, with the methylthio moiety in the para position. Vertical and adiabatic ionization energies are also calculated for both compounds.

Investigating the Effect of Emtricitabine Cocrystals with Aromatic Carboxylic Acids on Solubility and Diffusion Permeability

Emtricitabine (ECB), a nucleoside reverse-transcriptase inhibitor, is commonly used to prevent and treat HIV infection in both adults and children. The drug is categorized as a member of the Biopharmaceutics Classification System (BCS) class I with high solubility and moderate permeability. In continuation of the published research work on ECB cocrystals with para-substituted benzoic acids, multicomponent solid form screening was extended with aromatic carboxylic acids in order to improve the diffusion behavior of the native drug. Solvent-assisted grinding of equimolar ECB and aromatic carboxylic acids resulted in three anhydrous cocrystals with meta-hydroxybenzoic acid (MHB), vanillic acid (VAN), and ferulic acid (FER), in addition to three more cocrystal hydrates with para-methyl benzoic acid (PMB), para-chlorobenzoic acid (PCB), and para-nitrobenzoic acid (PNB). The cocrystals were characterized by single-crystal XRD, powder-XRD, DSC/TGA, and FT-IR spectroscopy. In all three cocrystals, the 2-aminopyrimidine···carboxylic acid heterosynthon was found to be prevalent similar to the reported ECB–benzoic acid cocrystal. In ECB–VAN and ECB–MHB, the ECB hydroxyl group was hydrogen-bonded to the hydroxyl groups of the coformers as well as to the carbonyl groups of other ECB molecules, and in ECB–FER, it was interlinked to the ECB carbonyl moiety only. In the other cocrystal hydrates, the ECB-OH group formed hydrogen bonds with water only. The solubility study in a pH 6.8 phosphate buffer indicated the solubility order of ECB > ECB–MHB > ECB–VAN > ECB–FER; i.e., the cocrystal decreased the solubility of the native drug. The diffusion study of ECB and its cocrystals was carried out using a Franz diffusion cell in a pH 6.8 buffer medium which suggests that ECB cocrystals decreased its diffusion rate compared to its native drug due to reduced concentration gradient/solubility and higher hydrophobic interactions.

Cytochrome P450-catalyzed oxidation of halogen-containing substrates

Cytochrome P450 (CYP) enzymes are heme-thiolate monooxygenases which catalyze the oxidation of aliphatic and aromatic C-H bonds and other reactions. The oxidation of halogens by cytochrome P450 enzymes has also been reported. Here we use CYP199A4, from the bacterium Rhodopseudomonas palustris strain HaA2, with a range of para-substituted benzoic acid ligands, which contain halogens, to assess if this enzyme can oxidize these species or if the presence of these electronegative atoms can alter the outcome of P450-catalyzed reactions. Despite binding to the enzyme, there was no detectable oxidation of any of the 4-halobenzoic acids. CYP199A4 was, however, able to efficiently catalyze the oxidation of both 4-chloromethyl- and 4-bromomethyl-benzoic acid to 4-formylbenzoic acid via hydroxylation of the α‑carbon. The 4-chloromethyl substrate bound in the enzyme active site in a similar manner to 4-ethylbenzoic acid. This places the benzylic α‑carbon hydrogens in an unfavorable position for abstraction indicating a degree of substrate mobility must be possible within the active site. CYP199A4 catalyzed oxidations of 4-(2′-haloethyl)benzoic acids yielding α-hydroxylation and desaturation metabolites. The α-hydroxylation product was the major metabolite. The desaturation pathway is significantly disfavored compared to 4-ethylbenzoic acid. This may be due to the electron-withdrawing halogen atom or a different positioning of the substrate within the active site. The latter was demonstrated by the X-ray crystal structures of CYP199A4 with these substrates. Overall, the presence of a halogen atom positioned close to the heme iron can alter the binding orientation and outcomes of enzyme-catalyzed oxidation.

COF-300 synthesis and colloidal stabilization with substituted benzoic acids.

Colloidal covalent organic framework (COF) synthesis enables morphological control of crystallite size and shape. Despite numerous examples of 2D COF colloids with various linkage chemistries, 3D imine-linked COF colloids are more challenging synthetic targets. Here we report a rapid (15 min-5 day) synthesis of hydrated COF-300 colloids ranging in length (251 nm-4.6 μm) with high crystallinity and moderate surface areas (150 m2 g-1). These materials are characterized by pair distribution function analysis, which is consistent with the known average structure for this material alongside different degrees of atomic disorder at different length scales. Additionally, we investigate a series of para-substituted benzoic acid catalysts, finding that 4-cyano and 4-fluoro substituted benzoic acids produce the largest COF-300 crystallites with lengths of 1-2 μm. In situ dynamic light scattering experiments are used to assess time to nucleation in conjunction with 1H NMR model compound studies to probe the impact of catalyst acidity on the imine condensation equilibrium. We observe cationically stabilized colloids with a zeta potential of up to +14.35 mV in benzonitrile as a result of the carboxylic acid catalyst protonating surface amine groups. We leverage these surface chemistry insights to synthesize small COF-300 colloids using sterically hindered diortho-substituted carboxylic acid catalysts. This fundamental study of COF-300 colloid synthesis and surface chemistry will provide new insights into the role of acid catalysts both as imine condensation catalysts and as colloid stabilizing agents.

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation.

GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.

Photolysis study of two indene-fused coumarin-based photoremovable protecting groups for potential biological applications

Two indene-fused coumarin-based photoremovable protecting groups (PPGs) 3a and 3b were synthesized. Their respective efficiencies of releasing para-substituted benzoic acids upon irradiation at 365 nm wavelength were studied. Results showed that upon photoexcitation, PPG 3a caged acids favor photocleavage process rather than fluorescence decay, leading to higher uncaging yields but lower fluorescence quantum yields than 3b caged counterparts. In contrast, PPG 3b caged acids prefer fluorescence over photocleavage, resulting in low uncaging yields. Therefore, 3a was employed to prepare a photoactivable camptothecin prodrug 3aCPT. Cell viability assay showed a statistically significant cytotoxicity difference of 3aCPT against human MDA-MB-468 cells before and after excitation at 405 nm, suggesting that 3a has good potential for pharmaceutical applications.

Nematicidal activity of furanoeremophilenes against Meloidogyne incognita and Nacobbus aberrans.

While searching for novel small molecules for new organic pesticide agents against plant-parasitic nematodes, we found that the hexane extract from the roots of Senecio sinuatos and its main secondary metabolite, 3β-angeloyloxy-6β-hydroxyfuranoeremophil-1(10)-ene (1), possess nematicidal activity against the second stage juvenile (J2) of Meloidogyne incognita and Nacobbus aberrans. Both species reduce yield of various vegetable crops. These results encouraged us to synthesize esters 3-9 formed by diol 2, obtained by alkaline hydrolysis of 1 and acetic anhydride, benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid, respectively. The nematicidal activity of these esters was evaluated and compared with that of the free benzoic acids. Natural product 1 and derivatives 2-9 were obtained and characterized by their physical and spectroscopic properties, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) experiments; X-ray diffraction analysis established their absolute configuration. The nematicidal activity of compounds 1-9 was assessed in vitro against M. incognita and N. aberrans J2 and was compared to activity shown by benzoic acid, 2-nitrobenzoic acid, 2-bromobenzoic acid, 4-nitrobenzoic acid, 4-bromobenzoic acid, and 4-methoxybenzoic acid. The esters suppressed nematodes more than free benzoic acid. Nacobbus aberrans J2 were suppressed, with compounds 5, 6, and 8 being the most active. Esters formed by 3β,6β-dihydroxyfuranoeremophil-1(10)-ene and ortho- or para-substituted benzoic acids containing electron acceptor groups had nematicidal activity against N. aberrans. These compound can potentially serve as a model for the development of new organic nematicidal agents. © 2022 Society of Chemical Industry.

The global profiling of alkaloids in Aconitum stapfianum and analysis of detoxification material basis against Fuzi

Aconitum alkaloids are versatile in chemical structures and are well known for their bioactivity and toxicity. Cases of analogs with closely similar structures or positional isomers are widespread in herbs of the Aconitum genus. It is still challenging to rapidly identify unknown compounds via mass spectrometry, especially positional isomers. Herein, to profile the alkaloids of Aconitum stapfianum that possess bioactivity against intoxication by the lateral root of Aconitum carmichaelii (Fuzi), a strategy was developed by carefully determining the fragmentation pathways of authentic standards. A series of rules was summarized and involved charge site effects, hydrogen bonding effects, competitive channels between charge-remote reactions and charge migration reactions, and fragment patterns exhibiting a “diamond shape”. Accordingly, a total of 124 alkaloids in A. stapfianum were tentatively characterized, including 85 potential new compounds and 24 sets of isomers. On the other hand, to explore the material basis of detoxification, a chemical constituent comparison was made between A. stapfianum and Fuzi, and principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were performed to identify markers that were different between the two . In total, 25 characteristic markers were identified to discriminate between these two herbal medicines, of which 14 compounds were specific for A. stapfianum and most of them were characteristic for a para-substituted benzoic acid ester at C-14.

INFLUENCE OF SUBSTITUTES ON THE RATE OF THE REACTION OF ORTHOSUBSTITUTED BENZOIC ACIDS WTH ANILINE, CATALYZED BY POLYBUTOXYTITANATES

The polybutoxytitanates catalysis of aniline acylation by orthosubstituted benzoic acids leads to the production of substituted benzanilides. Catalytic rate constants of the second order reaction (the first with respect to aniline and ortho-substituted benzoic acid; boiling ortho=xylene, 145°C) correlate well according to the Hammett and Bronsted equations with straight line segments with ρ=1.93 and α=0.66, in contrast to the reaction of aniline with meta- and parasubstituted benzoic acids and substituted anilines with benzoic acid. This dependence drops out 2=nitrobenzoic and 1=naphthoic acids, which have relatively low reactivity and the greatest steric hindrances both for nucleophilic attack by aniline and for possible coordination with catalytically active centers of the corresponding ortho-substituted titanium polybutoxybenzoates formed in situ.
 Based on these data, the previously proposed mechanism of bifunctional catalysis due to titanium polybutoxybenzoates and their complexes with meta- and parasubstitutedbenzanilides was supplemented by the possibility of the steric inhibition of reaction by the most bulky substituents and chelate structures formation of orthosubstituted benzoic acids and their anilides with individual titanium atoms of the catalyst, as well as the simulta­neous H-bonding of the amino group hydrogen atoms of aniline, which leads to its activation to a nucleophilic attack, with a carbonyl group and an orthopositioned substituent of the orthobenzoate ligand in the coordination sphere of titanium. Taking into account such chelation and steric barriers, as well as inhibition of acid catalysis due to the formation of the imide form of anilides, containing electron-withdrawing substituents, the equations for the rate constants of the catalytic reaction of ortho-substituted benzoic acids with aniline are derived, corresponding to the experimentally obtained Hammett dependence.

Isomechanical Groups in Molecular Crystals and Role of Aromatic Interactions

We have measured mechanical properties in molecular crystals of a series of para-substituted benzoic acids using nanoindentation. Two linear correlations were found for these materials: first betwe...

Application of Hammett equation to hydrogen bond interactions of benzoic acid in chloroform/water system and explanation for non-linear Hammett relation to partition coefficients for the same system

It is well known that benzoic acid distributes itself between chloroform and water. The partition coefficients (Kp) of seven different benzoic acids in chloroform/water are documented in the literature. Plausible hydrogen bonded structures of these seven benzoic acids with the two immiscible solvents were envisaged and the DFT calculation for these hydrogen bonds were carried out. Further, the conformity of Hammett relation to the hydrogen bond interactions was assessed. Application of Hammett equation to the hydrogen bonding of distribution of different para-substituted benzoic acids to these immiscible solvents is done for the first time. Further, an explanation for non-linear plot of partition coefficients logKp of para-substituted benzoic acids in chloroform-water system versus Hammett σ value has been explained for the first time.

INFLUENCE OF SUBSTITUTES ON THE RATE OF THE REACTION OF META- АND PARASUBSTITUTED BENZOIC ACIDS WTH ANILINE, CATALYZED BY POLYBUTOXYTITANATES

The polybutoxytitanates catalysis of acylation of anilines by meta- and parasubstituted benzoic acid results in substituted benzanilides. The rate constants of this second-order reaction (the first in terms of aniline and substituted benzoic acid; boiling ortho-xylene, 145 °С) correlates well according to the Hammett equation with two straight lines for individual groups of substituents with ρ = 1.76 (electron donors) and 0.12 (electron acceptors). Oxybenzoic and phthalic acids, that do not react with aniline and inhibit the interaction of the latter with benzoic acid, fall out of this dependence. Based on these data, as well as the results of a previous studies of the interaction of substituted anilines with a benzoic acid made under comparable conditions, a mechanism of bifunctional catalysis due to the formation of titanium polybutoxybenzoates in the first minutes of the reaction in situ — the true catalysts of the process, is proposed. The nucleophilic center of the catalyst can be represented by the carbonyl group of a substituted benzoate bound to a titanium atom, forming an H-bond with hydrogen atoms of the amino group of aniline, thus activated to react with a substituted benzoic acid. The titanium atoms of polytitanate (coordination catalysis) and their complexes with the resulting substituted benzanilides (acid catalysis) can act as the electrophilic center of a catalyst that activates the carbonyl group of a substituted benzoic acid to nucleophilic attack by aniline. A titanium atom bound to a substituted benzoate exhibits, depending on the nature of the substituent, various catalytic activity.

Adsorption of Polarized Molecules for Interfacial Band Engineering of Doped TiO2 Thin Films

Owing to their chemical and mechanical stability, metal-oxides have emerged as potential alternatives for conventional pure-metal and organic molecule-based solid-state electronic devices. Traditionally, band engineering of these metal-oxides has been performed to improve the efficiency of solar cells and transistors. However, recent advancements in the field of oxide-based electronic devices demand reversible band structure engineering for applications in next-generation adaptive electronics and memory devices. Therefore, this work aims to reversibly engineer the surface band structure of doped metal-oxides using stable organic ligands with weak dipoles. Para-substituted benzoic acid (BZA) ligands with positive and negative dipole moments were adsorbed in situ on the surface of TiO2:Ni2+ thin film to modify the interfacial dipole moment, and the valence band structure was probed using surface-sensitive ultraviolet photoelectron spectroscopy (UPS). UPS, paired with density functional theory (DFT) simulations, demonstrate the ability to selectively tune interfacial electronic/chemical landscapes with ligand-dependent dipole moment. The unique ability to reversibly tune the band bending at the organic–inorganic interface of doped metal-oxide semiconductors using molecular dipoles is expected to play a key role in the development of metal-oxide-based adaptive electronics that outperform the conventional polymer-based and Si-based devices.

Reactivity Parameters and Substitution Effect in Organic Acids

We investigate a few density functional theory-based reactivity indices of chemistry, with a view to arrive at an intercomparison and also consider their applications toward the problems of chemical significance. In particular, we propose to use the concepts of fugality and atom-atom polarizability to study the acidic strength of para-substituted benzoic acid derivatives. The nature of the variations and trends in the correlation of reactivity parameters and pKa values is shown to provide an insight into the applicability of these concepts to such reactions.

Unexpected Strong Acidity Enhancing the Effect in Protic Ionic Liquids Quantified by Equilibrium Acidity Studies: A Crucial Role of Cation Structures on Dictating the Solvation Properties.

The equilibrium acidities for several series of structural and electronic different organic acids were measured in 3-pyrrolidinium-based aprotic and protic ionic liquid (IL) analogues, that is, [Bmpy][NTf2], [BpyH][NTf2], and [PyH2][NTf2], by the UV-Vis method. The acidities of neutral acids are found to be much stronger in the protic ILs (PILs) than aprotic ILs (AILs), and the acidifying effect in the two PILs roughly increases proportionally to the number of protons in the cation of the PIL. On the other hand, interestingly, the cationic N+-H acids exhibit similar acidities in [Bmpy][NTf2] and [BpyH][NTf2] but much weaker than those in [PyH2][NTf2]. The Hammett ρ values for the acidic dissociation of para-substituted benzoic acids in two PILs are about the same as that in water (1.00) but significantly smaller than that in the AIL [Bmpy][NTf2] (2.66). The correlations between the acidities in the PILs and water show double-linear relationships with different slopes and intercepts for the neutral and cationic acids. These, together with previous observations in the PILs [DBUH][OTf] (DBU = 1,5-diazabicyclo(5.4.0)-5-undecene) and EAN (ethylammonium nitrate), clearly indicate that the structure of the cation plays a subtle but a crucial role on sensing the electronic nature of solutes and strongly affects the solvation behaviors of PILs.

Investigation of the requirements for efficient and selective cytochrome P450 monooxygenase catalysis across different reactions

The cytochrome P450 metalloenzyme (CYP) CYP199A4 from Rhodopseudomonas palustris HaA2 catalyzes the highly efficient oxidation of para-substituted benzoic acids. Here we determined crystal structures of CYP199A4, and the binding and turnover parameters, with different meta-substituted benzoic acids in order to establish which criteria are important for efficient catalysis. When compared to the para isomers, the meta-substituted benzoic acids were less efficiently oxidized. For example, 3-formylbenzoic acid was oxidized with lower activity than the equivalent para isomer and 3-methoxybenzoic acid did not undergo O-demethylation by CYP199A4. The structural data highlighted that the meta-substituted benzoic acids bound in the enzyme active site in a modified position with incomplete loss of the distal water ligand of the heme moiety. However, for both sets of isomers the meta- or para-substituent pointed towards, and was in close proximity, to the heme iron. The absence of oxidation activity with 3-methoxybenzoic acid was assigned to the observation that the CH bonds of this molecule point away from the heme iron. In contrast, in the para isomer they are in an ideal location for abstraction. These findings were confirmed by using the bulkier 3-ethoxybenzoic acid as a substrate which removed the water ligand and reoriented the meta-substituent so that the methylene hydrogens pointed towards the heme, enabling more efficient oxidation. Overall we show relatively small changes in substrate structure and position in the active site can have a dramatic effect on the activity.

Five benzoic acid derivatives: Crystallographic study using X-ray powder diffraction, electronic structure and molecular electrostatic potential calculation

Crystal structures of five ortho-, meta-, and para-substituted benzoic acid derivatives, 2-fluoro-4-hydroxymethyl benzoic acid (1), 4-chloro-3 nitrobenzoic acid (2), 5-bromo-2-methyl benzoic acid (3), 4-bromo-2 nitrobenzoic acid (4) and 4-chloro-2-iodobenzoic acid (5) have been determined using X-ray powder diffraction. DFT optimized molecular geometries of 1–5 agree closely with those obtained from the crystallographic study. The nature of intermolecular interactions in 1–5 has been analyzed through Hirshfeld surfaces and 2D fingerprint plots, and compared with that of unsubstituted benzoic acid compound. The crystal packing of 1–5 exhibits an interplay of intermolecular OH⋯O, CH⋯O and CH … X (X = F, Cl, Br) hydrogen bonds, and C-X (X = Cl, Br, I)⋯O halogen bonds, which assemble molecules into a supramolecular framework. Hydrogen- and halogen-bond based interactions in 1–5 have been complemented by the molecular electrostatic potential (MEP) surface calculation. The electronic structure of compounds (1–5) reveals that the estimated band gap in 4, with the nitro and bromo groups at the ortho and para positions with respect to the COOH group, is the lowest (2.72 eV) among the molecules; the corresponding value in the unsubstituted benzoic is 3.95 eV.

Cytochrome P450 CYP199A4 from Rhodopseudomonas palustris Catalyzes Heteroatom Dealkylations, Sulfoxidation, and Amide and Cyclic Hemiacetal Formation

The cytochrome P450 enzymes execute a range of selective oxidative biotransformations across many biological systems. The bacterial enzyme CYP199A4 catalyzes the oxidative demethylation of 4-methoxybenzoic acid. The benzoic acid moiety of the molecule binds in the active site of the enzyme such that the functional group at the para-position is held close to the heme iron. Therefore, CYP199A4 has the potential to catalyze alternative monooxygenase reactions with different para-substituted benzoic acid substrates such as thioethers and alkylamines. The oxidation of 4-methyl- and 4-ethyl-thiobenzoic acids by CYP199A4 resulted in sulfur oxidation. 4-Ethylthiobenzoic acid sulfoxidation and 4-ethylbenzoic acid hydroxylation by CYP199A4 occurred with high enantioselectivity (>74% enantiomeric excess). By way of contrast, CYP199A4 catalyzed exclusive oxidative N-demethylation over N-oxide formation with 4-methyl- and 4-dimethylaminobenzoic acids. Unexpectedly acetamide formation by CYP199A4 competes with dealkyla...