The basicities of simple organic bases – aliphatic and aromatic amines, amidines, phosphazenes, as well as saturated and unsaturated nitrogen heterocycles – are examined in acetonitrile, dimethyl sulfoxide, tetrahydrofuran, water and the gas phase. The basicities (pKaH values) of conjugate acids of a large variety of bases in these media are presented and discussed. Equations employing easily usable structural descriptors have been derived for approximately converting basicities from acetonitrile to other solvents. Recommendations are given on their practical use and a number of pKaH values that are experimentally unavailable are estimated from these relationships. An important part of the minireview is a large compilation of pKaH and GB values of the compounds in solvents and the gas phase, respectively, as well as the revised basicity scale in acetonitrile, now containing more than 270 pKaH values.

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Monoamine oxidases (MAOs) are flavoenzymes important in regulating amine neurotransmitter levels and are the central pharmacological targets in treating depression and Parkinson's disease. On the basis of quantum chemical calculations, we have proposed a new two‐step hydride mechanism for the MAO‐catalysed oxidative deamination of amines. In the rate‐limiting first step, through its N5 atom, the flavin abstracts a hydride anion from the substrate α‐carbon atom and forms a strong covalent adduct with the thus created cation. This is followed by flavin N1 deprotonation of the substrate amino group, facilitated with two active‐site water molecules, to produce fully reduced flavin, FADH2, and neutral imine. We have demonstrated that our mechanism is in agreement with available experimental data and provided evidence against both traditional polar nucleophilic and single‐electron radical pathways. These results provide valuable information for mechanistic studies on other flavoenzymes and for the design of new antidepressants and antiparkinsonian drugs.

In this work we explored the relationship between the structure and solvent effects on the basicity of a large selection of conjugated N‐heterocyclic nitrogen bases in different media: the polar aprotic solvent acetonitrile, the polar protic solvent water and the gas phase. Altogether, 58 previously unpublished basicity values in different media for 39 compounds are presented, including 30 experimentally determined pKa values in acetonitrile. We present the pKa and gas‐phase basicity values for quino[7,8‐h]quinoline, which is one of the most basic conjugated nitrogen heterocyclic compounds without basicity‐enhancing substituents. The trends in basicity are rationalized by comparing the basicity data of related compounds in different solvents, as well as by using isodesmic reactions. The gas‐phase basicity is predominantly determined by the ability of a molecule to disperse the excess positive charge over a large number of atoms. In solution the situation is less clear and smaller systems with localized charge often lead to higher basicities because of solvent effects. In particular, it was found that the fusion of an additional benzene ring does not always lead to an increase in basicity in solution: its effect can be either basicity‐increasing or ‐decreasing, depending on the ring size, number and position of nitrogen atoms and medium. A correlation between the measured pKa values in MeCN and in water suggests that these two different solvents exert a similar effect on the basicity of the studied heterocycles.

Monoamine oxidases (MAOs) A and B are flavoenzymes responsible for the metabolism of biogenic amines such as dopamine, serotonin and noradrenaline. In this work, we present a comprehensive study of the rate-limiting step of dopamine degradation by MAO B, which consists in the hydride transfer from the methylene group of the substrate to the flavin moiety of the FAD prosthetic group. This article builds on our previous quantum chemical study of the same reaction using a cluster model (Vianello et al., Eur J Org Chem 2012; 7057), but now considering the full dimensionality of the hydrated enzyme with extensive configurational sampling. We show that MAO B is specifically tuned to catalyze the hydride transfer step from the substrate to the flavin moiety of the FAD prosthetic group and that it lowers the activation barrier by 12.3 kcal mol⁻¹ compared to the same reaction in aqueous solution, a rate enhancement of more than nine orders of magnitude. Taking into account the deprotonation of the substrate prior to the hydride transfer reaction, the activation barrier in the enzyme is calculated to be 16.1 kcal mol⁻¹, in excellent agreement with the experimental value of 16.5 kcal mol⁻¹. Additionally, we demonstrate that the protonation state of the active site residue Lys296 does not have an influence on the hydride transfer reaction.

An efficient but reasonably accurate B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) computational procedure showed that pentasubstituted cyclopentadienes such as (CN)5C5H, (NO2)5C5H, and (NC)5C5H containing strongly electron-withdrawing groups are neutral organic superacids of unprecedented strength. The boldface denotes the atom attached to the cyclopentadiene framework. All of them exhibit prototropic tautomerism by forming somewhat more stable structures with C=NH, NO2H, and N=CH exocyclic fragments, respectively. The acidity (DeltaH(acid)) of these is lower, but only to a rather small extent. The DeltaH(acid) enthalpies of these last three tautomers are estimated to be 271, 276, and 282 kcal mol(-1), respectively. Hence, the most stable tautomers of (CN)5C5H and (NC)5C5H represent a legitimate target for synthetic chemists. On the other hand, (NO2)5C5H is less suitable for practical applications, because of its high energy density. The origin of the highly pronounced acidity of these compounds was analyzed by using the recently developed triadic formula. It is found that very high Koopmans' ionization energy (IE)n(Koop) of conjugate bases exerts a decisive influence on acidity. It follows as a corollary that the overwhelming effect leading to very high acidity is due to the properties of the final state. An alternative picture is offered by homodesmotic reactions, wherein the cyclic systems are compared with their linear counterparts. It is found that the acidity of cyclopentadiene (CP) is a consequence of aromatic stabilization in the CP- anion. The extreme acidity of pentacyanocyclopentadiene (CN)5C5H is due to aromatization of the five-membered ring and a strong anionic resonance effect in the resultant conjugate base. The neutral organic superacids predicted by the present calculations may help to bridge the gap between existing very strong acids and bases.

Monoamine oxidase (MAO), which exists in two isozymic forms, MAO A and MAO B, is an important flavoenzyme responsible for the metabolism of amine neurotransmitters such as dopamine, serotonin and norepinephrine. Despite extensive research effort, neither the catalytic nor the inhibition mechanisms of MAO have been completely understood. There has also been dispute with regard to the protonation state of the substrate upon entering the active site, as well as the identity of residues that are important for the initial deprotonation of irreversible acetylenic inhibitors, in accordance with the recently proposed mechanism. Therefore, in order to investigate features essential for the modes of action of MAO, we have calculated pK a values of three relevant tyrosine residues in the MAO B active site, with and without dopamine bound as the substrate (as well as the pK a of the dopamine itself in the active site). The calculated pK a values for Tyr188, Tyr398 and Tyr435 in the complex are found to be shifted upwards to 13.0, 13.7 and 14.7, respectively, relative to 10.1 in aqueous solution, ruling out the likelihood that they are viable proton acceptors. The altered tyrosine pK a values could be rationalized as an interplay of two opposing effects: insertion of positively charged bulky dopamine that lowers tyrosine pK a values, and subsequent removal of water molecules from the active site that elevates tyrosine pK a values, in which the latter prevails. Additionally, the pK a value of the bound dopamine (8.8) is practically unchanged compared to the corresponding value in aqueous solution (8.9), as would be expected from a charged amine placed in a hydrophobic active site consisting of aromatic moieties. We also observed potentially favorable cation-π interactions between -NH 3 + group on dopamine and aromatic moieties, which provide stabilizing effect to the charged fragment. Thus, we offer here theoretical evidence that the amine is most likely to be present in the active site in its protonated form, which is similar to the conclusion from experimental studies of MAO A (Jones et al. J. Neural Trans. 2007, 114, 707-712). However, the free energy cost of 3 transferring the proton from the substrate to the bulk solvent is only 1.9 kcal mol -1 , leaving open the possibility that the amine enters the chemical step in its neutral form. In conjunction with additional experimental and computational work, the data presented here should lead towards a deeper understanding of mechanisms of the catalytic activity and irreversible inhibition of MAO B, which can allow for the design of novel and improved MAO B inhibitors.

The bis-guanidino compound H(2)C{hpp}(2) (I; hppH = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) has been converted to the monocation [I-H](+) and isolated as the chloride and tetraphenylborate salts. Solution-state spectroscopic data do not differentiate the protonated guanidinium from the neutral guanidino group but suggest intramolecular "-N-H...N=" hydrogen bonding to form an eight-membered C(3)N(4)H heterocycle. Solid-state CPMAS (15)N NMR spectroscopy confirms protonation at one of the imine nitrogens, although line broadening is consistent with solid-state proton transfer between guanidine functionalities. X-ray diffraction data have been recorded over the temperature range 50-273 K. Examination of the carbon-nitrogen bond lengths suggests a degree of "partial protonation" of the neutral guanidino group at higher temperatures, with greater localization of the proton at one nitrogen position as the temperature is lowered. Difference electron density maps generated from high-resolution X-ray diffraction studies at 110 K give the first direct experimental evidence for proton transfer in a poly(guanidino) system. Computational analysis of I and its conjugate acid [I-H](+) indicate strong cationic resonance stabilization of the guanidinium group, with the nonprotonated group also stabilized, albeit to a lesser extent. The maximum barrier to proton transfer calculated using the Boese-Martin for kinetics method was 2.8 kcal mol(-1), with hydrogen-bond compression evident in the transition state; addition of zero-point vibrational energy values leads to the conclusion that the proton transfer is barrierless, implying that the proton shuttles freely between the two nitrogen atoms. Calculations determining the gas-phase proton affinity and the pK(a) in acetonitrile both indicate that compound I should behave as a superbase. This has been confirmed by spectrophotometric titrations in MeCN using polyphosphazene references, which give an average pK(a) of 28.98 +/- 0.05. Triadic analysis indicates that the dominant term causing the high basicity is the relaxation energy.