Nitration of Phenol and Substituted Phenols with Dilute Nitric Acid Using Phase-Transfer Catalysts

Carbanionic intermediates play a central role in the catalytic transformations of amino acids performed by pyridoxal-5′-phosphate (PLP)-dependent enzymes. Here, we make use of NMR crystallography—the synergistic combination of solid-state nuclear magnetic resonance, X-ray crystallography, and computational chemistry—to interrogate a carbanionic/quinonoid intermediate analogue in the β-subunit active site of the PLP-requiring enzyme tryptophan synthase. The solid-state NMR chemical shifts of the PLP pyridine ring nitrogen and additional sites, coupled with first-principles computational models, allow a detailed model of protonation states for ionizable groups on the cofactor, substrates, and nearby catalytic residues to be established. Most significantly, we find that a deprotonated pyridine nitrogen on PLP precludes formation of a true quinonoid species and that there is an equilibrium between the phenolic and protonated Schiff base tautomeric forms of this intermediate. Natural bond orbital analysis indicates that the latter builds up negative charge at the substrate Cα and positive charge at C4′ of the cofactor, consistent with its role as the catalytic tautomer. These findings support the hypothesis that the specificity for β-elimination/replacement versus transamination is dictated in part by the protonation states of ionizable groups on PLP and the reacting substrates and underscore the essential role that NMR crystallography can play in characterizing both chemical structure and dynamics within functioning enzyme active sites.

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“…36,62 2-Aminophenol was prepared 15 N labeled ( 15 N-2AP) following literature protocols 63,64 as described in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

NMR Crystallography of a Carbanionic Intermediate in Tryptophan Synthase: Chemical Structure, Tautomerization, and Reaction Specificity

et al. 2016

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“…Tetraalkylammonium halides, for example, were used as PTCs, for halogenation in a biphasic system consisting of water and a chlorinated solvent, where besides acting as transfer agents they could also act as halogenating agents. [125][126][127] In the presence of Bu 4 NBr, oxybromination of non-activated aromatic molecules occurred, and a 50-70 times rate acceleration was determined in the bromination of benzene. [128] The instead of Br À ) had no effect on the reaction rate.…”

Section: Oxidative Halogenation "On Water"mentioning

confidence: 99%

Oxidative Halogenation with “Green” Oxidants: Oxygen and Hydrogen Peroxide

2009

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It is difficult to imagine organic chemistry without organo-halogen compounds and the molecular halogens needed for their preparation. The halogens have very different reactivity, with iodine usually requiring some form of activation, while others are reactive and hazardous chemicals. To avoid their use, various modified reagents have been discovered (N-bromo- and N-chlorosuccinimide, Selectfluor..), but halogens are used to prepare these reagents and when they are used the atom economy is poor. A better approach, which is based on biomimetric research on oxidative halogenation in nature, consists of generating the halogenating reagent in situ under acidic conditions from a halide salt. The result of such a reaction has been halogenation with 100 % halogen atom economy. Suitable oxidants for the oxidation of halides are hydrogen peroxide and oxygen.

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“…In the last decade, much effort has been made on nitration of phenols. [13][14][15][16][17][18][19][20] A variety of acidic nitrating agents, including concentrated nitric acid, nitrogen oxides, anhydrides or triflates, and solid acids have been employed. Also many methods have been reported using metal nitrates as source of nitronium ion.…”

Section: Introductionmentioning

confidence: 99%

A practical approach for regioselective mono-nitration of phenols under mild conditions

Chen¹,

Liu²,

Zhou³

et al. 2014

Arkivoc

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Nitration of Phenol and Substituted Phenols with Dilute Nitric Acid Using Phase-Transfer Catalysts

Cited by 39 publications

References 36 publications

NMR Crystallography of a Carbanionic Intermediate in Tryptophan Synthase: Chemical Structure, Tautomerization, and Reaction Specificity

NMR Crystallography of a Carbanionic Intermediate in Tryptophan Synthase: Chemical Structure, Tautomerization, and Reaction Specificity

Oxidative Halogenation with “Green” Oxidants: Oxygen and Hydrogen Peroxide

A practical approach for regioselective mono-nitration of phenols under mild conditions

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