Hydrogen-Bond Acidity of OH Groups in Various Molecular

Article pubs.acs.org/JPCA

Hydrogen-Bond Acidity of OH Groups in Various Molecular Environments (Phenols, Alcohols, Steroid Derivatives, and Amino Acids Structures): Experimental Measurements and Density Functional Theory Calculations Jérôme Graton,* François Besseau, Anne-Marie Brossard, Eloïse Charpentier, Arnaud Deroche, and Jean-Yves Le Questel* UMR CNRS 6230, Université de Nantes, CEISAM, 2 rue de la Houssinière, 44322 Nantes cedex 3, France S Supporting Information *

ABSTRACT: The hydrogen-bond (H-bond) donating strengths of a series of 36 hydroxylic H-bond donors (HBDs) with N-methylpyrrolidinone have been measured in CCl4 solution by FTIR spectrometry. These data allow the definition of a H-bond acidity scale named pKAHY covering almost three pK units, corresponding to 16 kJ mol−1. These results are supplemented by equilibrium constants determined in CH2Cl2 for one-third of the data set to study compounds showing a poor solubility in CCl4. A systematic comparison of these experimental results with theoretical data computed in the gas phase using DFT (density functional theory) calculations has also been carried out. Quantum electrostatic parameters appear to accurately describe the H-bond acidity of the hydroxyl group, whereas partial atomic charges according to the Merz−Singh−Kollman and CHelpG schemes are not suitable for this purpose. A substantial decrease of the H-bond acidity of the OH group is pointed out when the hydroxyl moiety is involved in intramolecular H-bond interactions. In such situations, the interactions are further characterized through AIM and NBO analyses, which respectively allow localizing the corresponding bond critical point and the quantification of a significant charge transfer from the available lone pair to the σ*OH antibonding orbital. Eventually, the H-bond ability of the hydroxyl groups of steroid derivatives and of lateral chains of amino acids are evaluated on the basis of experimental and/or theoretical data.

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INTRODUCTION The hydrogen bond is an attractive interaction between a Hbond donor (HBD) XH and a H-bond acceptor (HBA), involving forces of an electrostatic origin and those arising from charge transfer between the donor and acceptor entities.1 Therefore, in the enlarged Lewis definition of acidity and basicity, where acids accept and bases donate electron density, the HBD is a Lewis acid because it accepts electron density and the HBA is a Lewis base because it donates electron density. Hydrogen bonding can thus be considered a special class of Lewis acid−base interaction. In terms similar to the definition of Lewis basicity advised by the International Union of Pure and Applied Chemistry (IUPAC)2 “comparative measures of [H-bond basicity] are provided by the equilibrium constants K for [1:1 H-bonded complex] formation for a series of [HBAs] with a common reference [HBD].” In view of the importance of hydrogen bonding, the characterization of H-bond basicity has been extensively studied, leading to the construction of several H-bond basicity scales.3−7 Among those, to the best of our knowledge, the pKBHX scale constitutes the largest and the most diversified H-bond basicity database.7 In the same vein, comparative measurements of H-bond acidity can be obtained through the equilibrium constants K for 1:1 H-bonded complex formation for a series of HBDs with a common reference HBA. © 2013 American Chemical Society

Such H-bond acidity studies are more scarce and only a few of them have attempted to build H-bond acidity scales, the most extensive study in this context remaining the ones conducted in Abraham’s group, with the log Kα and log KHA scales.5,8 In this early study, the data correspond to 1:1 complexation constants measured for a series of H-bond acids against a given H-bond base, N-methylpyrrolidinone. By opposition to this 1:1 H-bond acidity scale, an “overall” or “effective” H-bond acidity scale, Σα2H,9 has later been defined by Abraham, afterward simplified as A10 and referring to the situation in which a solute with n HBD groups, a polyfunctional H-bond acid, is surrounded by an excess of HBA groups in such a way that a H-bonded complex of 1(HBD):n(HBA) stoichiometry can potentially be formed. Although they are still log K related, they do not, however, obey the IUPAC definition of acidity. For polyfunctional acids, they evidently differ from 1:1 scales, because they correspond to 1:n complexation. The original method, obtained from gas chromatographic retention data,11 has then been considerably extended.12−18 More recently, a method relying on measurements of the differences in the 1H NMR chemical Received: October 9, 2013 Revised: November 25, 2013 Published: November 25, 2013 13184

dx.doi.org/10.1021/jp410027h | J. Phys. Chem. A 2013, 117, 13184−13193

The Journal of Physical Chemistry A

Article

C(HBD···NMP) K = ‐1 C HMD·CNMP dm mol

shifts of solutes protic hydrogen in DMSO and CDCl3 has been shown to be directly related to the overall H-bond acidity.19 Nevertheless, the standard deviation of 0.053 units in A obtained through the training equation set up in this work corresponds to a standard deviation of 0.25 in log K units, given the definition of A by Abraham. Therefore, it is our opinion that this methodology gives more qualitative tendencies than quantitative values needed for a fine-tuning of H-bond properties. Even if the chemical diversity of H-bond donors is not as important as observed for H-bond acceptors, the data available so far for H-bond acidity are not sufficient and arise from too different studies and techniques. In this work, we have investigated the H-bond acidity properties of hydroxylic compounds through homogeneous and accurate experimental measurements and computational chemistry calculations. Obviously, several theoretical attempts to predict as accurately as possible the experimental H-bond acidity are found in the literature. These studies are based not only on the utilization of various quantum descriptors, such as the electrostatic potential computed at the molecular surface,20,21 at the nuclei,21,22 and at a defined point,23 but also on atoms in molecules (AIM) derived parameters,24 the electrophilic superdelocalizability,25 or the hydrogen-bond energies of complexation.26,27 In the current paper, we have focused on quantum electrostatic parameters. After calibration carried out on usual hydroxylic compounds, we have investigated the H-bond acidity of a few hydroxylic steroids. Finally, because it is generally admitted that the local molecular environment can have huge impacts on Hbond properties, we have studied, through theoretical calculations, the H-bond acidity of hydroxylic amino acids in various surroundings, isolated or inserted in α-helix or β-sheets structures.

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3

=

0 0 C HBD(C NMP − C HBD + C HBD)

pKAHY = −log10 KAHY = +log10 K

(2) (3)

In eq 2, CHBD···NMP, CHBD, and CNMP are the equilibrium concentrations, on the molar scale, of the complex, the H-bond donor, and the H-bond acceptor NMP, respectively, and C0HBD and C0NMP are the initial concentrations, obtained by weighing. When the equilibrium is established, the H-bond donor concentration, CHBD, is obtained from the Beer−Lambert law (eq 4) using the monitoring of the free OH absorption of the studied HBD around 3600−3620 cm−1. In addition, the preliminary measurement of the molar absorption coefficient εOH is necessary for each HBD, as well as the determination of the experimental concentration avoiding their self-association to prevent the formation of 1:n H-bond complexes

A = εOH SC HBD

(4)

Lastly, the frequency shift, ΔνOH, upon complexation was measured because it appears as a useful and instructive spectroscopic scale of H-bond acidity. Computational Methods. All simulations were achieved with the Gaussian 09 program package,28 applying default procedures, integration grids, algorithms, and parameters. The MPWB1K functional29 has been selected, in combination with the 6-31+G(d,p) basis set, to carry out the conformational study of the H-bond donors. The solvent (CCl4) effects were not taken into account during calculations, carried out in the gas phase. The vibrational spectrum was systematically computed on the minimized structures to check that there was no imaginary vibrational mode. On the basis of the main electrostatic character of the H-bond interaction, several electrostatic descriptors were tested to determine which one is the most properly correlated to the experimental H-bond acidity. The electrostatic potential values were calculated (i) at the nuclei, VH, because Galabov previously found very good linear correlations of this descriptor with either experimental or theoretical H-bond acidity parameters,30−32 (ii) at a distance of 0.55 Å, Vα(r), from the hydroxyl hydrogen atom along the OH bond, as suggested by Kenny,23 and (iii) at the electronic isodensity surface of 0.001 e bohr−3, VS,max, as recommended by Bader.33 Atomic partial charges fitted to the electrostatic potential according to the schemes of Merz−Singh−Kollman (MK)34,35 and Breneman and Wiberg (CHelpG)36 were also estimated. When relevant, the relative population of the various conformers was evaluated from the computed Gibbs energies through a Boltzmann distribution (eq 5) and the theoretical descriptors weighted by these populations.

EXPERIMENTAL SECTION

Chemicals and FTIR Spectrometry. All hydroxylic compounds were commercial products purified by standard procedures and carefully dried. N-methylpyrrolidinone, NMP 99.5+% of purity, was also stored over molecular sieves and in darkness to prevent its deterioration. Carbon tetrachloride solvent, of spectroscopic grade, was kept for several days over freshly activated 4 Å molecular sieves before use. The handling of all chemicals and their CCl4 solutions and the filling of the cells for IR measurements were performed in the dry atmosphere of a glovebox at room temperature. IR spectra were recorded in carbon tetrachloride solutions with a Fourier-transform spectrometer Bruker Tensor 27 at a resolution of 1 cm−1. An Infrasil quartz cell, of S = 1 cm path length and thermostated at 25.0 ± 0.2 °C by a Peltier effect regulation, was used for the studies of H-bond complexation. H-Bond Equilibrium Constant Determination. Dilute CCl4 solutions of the studied hydroxylic HBDs and NMP, the selected reference HBA, were prepared to only observe 1:1 Hbonded HBD···NMP complexes in solution. With these conditions, a thermodynamic H-bond acidity scale, pKAHY, can be defined for organic HBDs as the logarithm of the equilibrium constant K at 298 K (eqs 1−3). HBD + NMP ⇌ HBD···NMP

0 C HBD − C HBD

pi =

e−ΔGi / RT n ∑i = 1 e−ΔGi / RT

(5)

An investigation of the charge transfer component between the acceptor lone pair and the σ* donor antibonding orbital was achieved through a natural bond orbital analysis.37,38 The corresponding interaction energies E(2)n→σ* were evaluated from the second-order perturbation theory. An analysis of electron densities was computed at the critical points of

(1) 13185



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Table 1. Experimental Spectroscopic Features, νOH, εOH, and ΔνOH, H-Bond Acidity, pKAHY, log KH A , and ΔGAHY, and Protonation Properties, pKa, of H-Bond Donors under Study compound 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

3,4,5-trichlorophenol 3,5-dichlorophenol 4-bromophenol 4-chlorophenol 4-fluorophenol 1-naphthol 3,5-dimethoxyphenol 3-isoropylphenol 4-methoxyphenol phenol 3-tert-butylphenol 4-methylphenol 4-tert-butylphenol 2,3,4,5,6-pentachlorophenol 3,5-diisopropylphenol 3,4,5-trimethylphenol 2,4-dichlorophenol

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

1,1,1,3,3,3-hexafluoroisopropanol 2,2,2-trifluoroethanol 3-nitrobenzyl alcohol 2,2,2-trichloroethanol 2,2-dichloroethanol 3-methoxybenzyl alcohol benzyl alcohol testosterone androstanolone allyl alcohol ethynyl-c-pentanol ethanol borneol c-pentanol mifepristone c-hexanol 2-butanol

35 36

acetone oxime c-hexanone oxime

νOHa 3599 3602 3608 3608 3614 3608 3611 3611 3618 3612 3612 3614 3613 3523 3612 3614 3549 3618 3620 3635f 3600 3601 3616g 3618g 3630 3617 3621 3611 3636 3631 3626 3617 3623 3629 3608 3607

εOHb

pKAHY

Phenols 252 3.49 251 3.23 271 2.66 261 2.64 236 2.38 238 2.31 238 2.18 247 2.07 248 2.07 248 2.06 250 2.06 253 2.05 225 2.05 256 2.03 242 1.96 239 1.87 210 1.77 Aliphatic Alcohols 87 3.10 125 1.98 73 1.79 138 1.67 108 1.48 76 1.06 73 1.03 49 0.93 70 0.86 58 0.85 114 0.85 57 0.75 62 0.74 71 0.73 98 0.68 64 0.67 51 0.65 Oximes 208 1.03 238 1.02

ΔGAHYc

ΔνOHa

log KHA

pKa

−19.9 −18.4 −15.2 −15.1 −13.6 −13.2 −12.4 −11.8 −11.8 −11.8 −11.8 −11.7 −11.7 −11.6 −11.2 −10.7 −10.1

459 436 378 373 359 362 341 332 331 343 329 331 333 451 319 319 392

2.69 2.49 2.02 2.01 1.82 1.72 n.d.d n.d.d 1.56 1.66 n.d.d 1.54 1.49 1.46 n.d.d 1.43e n.d.d

7.84 8.18 9.34 9.42 9.46 9.3 9.35 10.16 10.21 9.99 10.12 10.26 10.39 4.5 n.d.d 10.25 7.85

−17.7 −11.3 −10.2 −9.5 −8.4 −6.1 −5.9 −5.3 −4.9 −4.9 −4.9 −4.3 −4.2 −4.2 −3.9 −3.8 −3.7

440 289 245 285 254 197 193 194 190 186 211 183 183 176 217 174 173

2.47 1.53 n.d.d 1.22 n.d.d n.d.d 0.72e n.d.d n.d.d n.d.d n.d.d 0.44 n.d.d n.d.d n.d.d n.d.d n.d.d

9.3 12.39 n.d.d 12.24 12.91 n.d.d 15.4 n.d.d n.d.d 15.5 n.d.d 15.93 n.d.d n.d.d n.d.d n.d.d 17.6

−5.9 −5.8

277 275

n.d.d n.d.d

n.d.d n.d.d

a In cm−1. bIn dm3 mol−1 cm−1. cΔGAHY/kJ mol−1 = −RT ln(10)pKAHY = −5.708 pKAHY at 298 K. dNot determined. eSecondary log KHA value. fA secondary band at 3617 cm−1 is observed in the IR spectra. gA secondary band at 3635 cm−1 is observed in the IR spectra.

interactions, within the framework of the AIM theory39,40 with the AIM2000 set of programs.41

The study of other oxime derivatives could be of interest in a future work, cyano-oximes for example showing a higher Hbond ability than aldoximes, ketoximes, and amidoximes.42 When available, the log KHA values previously determined by Abraham et al.8 are also specified in Table 1. The log KHA scale (and its linear transform α2H) has been built against a great number of reference HBAs and the combination of many reference bases requires a statistical treatment of log K values within the literature so that the determination of new values is not straightforward. Moreover, equilibrium constants toward NMP in 1,1,1-trichloroethane determined previously43 are also closely correlated to log KHA values.8 However, this solvent is nowadays unavailable for toxicological reasons, and the log KHA scale can no more be extended through this method. As illustrated by eq 6, a strong correlation is nevertheless found with the pKAHY series of data, because near 99% of the pKAHY variance (100 r2) is explained by log KHA the standard

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RESULTS AND DISCUSSION 1. Experimental Results. Thermodynamic H-Bond Acidity Scale. The training data set studied in this work includes 17 phenols, 17 aliphatic alcohols, and 2 oximes. In a preliminary step, the IR spectroscopic features of the OH stretching vibration were determined for each HBD. The stretching frequencies, νOH, and molar absorption coefficients, εOH, were measured in dilute CCl4 solutions at 25.0 °C, and are gathered in Table 1, with the frequency shifts of the HBD stretching band, ΔνOH, upon complexation. The experimental equilibrium constants of complexation with NMP, pKAHY, are also reported in Table 1, spanning almost 3 pK units corresponding to an energetic range around 16 kJ mol−1. Phenol derivatives are significantly stronger HBDs than aliphatic alcohols and oximes. 13186



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deviation, s, being just slightly higher than the admitted experimental error (±0.04). This relationship therefore allows an extension of the log KHA scale when necessary. On the other side, the log KHA data, published for 75 supplementary hydroxyl compounds,8 can be used to calculate secondary pKAHY H-bond acidity values through eq 6. These values are gathered in the Supporting Information.

upward deviation from the regression line, whereas the two other benzylalcohols (23 and 24) clearly obey the pKAHY/ΔνOH relationship (7). Notwithstanding, because the ΔνOH determination does not require any accurate concentration, the established relationship appears useful for a rough estimation of H-bond acidity of compounds that are not soluble enough in CCl4 to make an accurate measurement of the equilibrium constant of complexation. Moreover, it is also important for toxic compounds to handle much less of the compound and to reduce the measurement time. For these reasons, only the ΔνOH measurement was carried out for alcohols 38 and 39.

pKAHY = 1.212 log KAH + 0.183 n = 17, r 2 = 0.988, s = 0.06

(6)

Spectroscopic H-Bond Acidity Scale. For H-bond basicity characterization, the IR frequency shift, ΔνOH, of the OH stretching vibration measured upon hydrogen bonding can be considered as a spectroscopic estimate of “basicity”,7 and the deviations from the pKBHX−ΔνOH relationships can be rationalized for example by steric effects,44 or three-center hydrogen bonds.45,46 Considering here the H-bond acidity, we may wonder whether the frequency shifts measured for the different HBDs bound to a common HBA (NMP) are also correlated to the H-bond acidity scale. A good correlation is indeed found for 30 hydroxyl compounds among the 36 molecules under study (80% of the data set), as shown in Figure 1. A significant deviation from the regression line is,

pKAHY = 0.009ΔνOH − 0.843 n = 30, r 2 = 0.9747, s = 0.13

(7)

Comparison with the Brønsted Proton Acidity Scale. The aqueous47,48 or gas-phase49 proton acidity or basicity can sometimes be considered as a reasonable descriptor of H-bond acidity or basicity. Provided that a homogeneous chemical family is under study, this assumption can indeed be satisfied, but it is no more valid for extended data sets.7 In this work, the hydroxyl family under study appears homogeneous enough to show a reasonable correlation between H-bond and Brønsted acidity values for 22 phenols and alcohols (Figure 2). However,

Figure 2. Plot of pKAHY versus pKa Brønsted acidity for 22 hydroxylic compounds (◆). The chlorophenols 14 and 17 (▲) showing a potential OH···Cl intramolecular interaction deviate from the general relationship.

Figure 1. Plot of pKAHY versus Δν(OH) frequency shift for 30 hydroxylic compounds. The two oximes (■) appear belonging to another chemical family than the phenols and aliphatic alcohols one (◆). The compounds (▲) showing a potential OH···Cl or OH···π intramolecular interaction deviate from the general relationship.

the standard deviation found, s = 0.29, prevents any accurate estimation of the H-bond acidity of hydroxyl compounds from their pKa values. Eventually, the two chlorophenols 14 and 17 deviate once again significantly from the regression line. The electron withdrawing effect of the five chlorine atoms leads to the weakest pKa value in the series for 14, but it is overcompensated by the OH···Cl intramolecular H-bond in CCl4 solution considering its H-bond acidity. Considering Figure 2, the vertical deviation from the pKAHY−pKa correlation observed for 17 and 14, with their two and five chlorine substituents, allows us to estimate the loss of H-bond donating capacity to be around one and even two pK units, respectively. Dichloromethane Solution Measurements. Owing to their low solubility in CCl4, the H-bond acidity properties of some compounds are not directly reachable in this solvent. However, their solubility can be higher in solvents such as dichloromethane in which equilibrium constants can therefore be

however, observed (i) for the two oxime derivatives (35 and 36) which do not seem to belong to the phenol and aliphatic alcohol family and would deserve a further study, and (ii) for 2,3,4,5,6-pentachlorophenol (14), 2,4-dichlorophenol (17), ethynyl-c-pentanol (28), and mifepristone (32). For the latter set, this behavior can be assigned to an intramolecular interaction occurring between the hydroxyl moiety and either a chlorine atom or a π site in CCl4 solutions (see below). Indeed, the high frequency shift ΔνOH values suggest a stronger H-bond acidity than experimentally measured, the first parameter being the reflection of the strength of the interaction once it is established whereas the pKAHY data take into account the energetic penalty induced by the preliminary dissociation of the intramolecular interaction. Hence, downward deviations from the pKAHY−ΔνOH plot are observed in these cases. On the contrary, the 3-nitrobenzylalcohol (20) shows an unexplained 13187



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However, on the example of the pKAHY−Vα(r) plot (Figure 4A), significant deviations from the regression line appear for the two o-chlorophenols 14 and 17, previously highlighted to have a particular behavior from their ΔνOH and pKa parameters. When these two compounds are excluded from the data set, a significant improvement of the statistics is observed. Indeed, more than 98% of the variance (=100r2) of the H-bond acidity parameter is explained by the electrostatic parameter Vα(r) (97% and 96% for VS,max and EPNUC, respectively). Although limited to hydroxyl HBDs, these results yield a robust equation including a significant number of points over an energetic scale range of 16 kJ mol−1. Correlated with log Kα,5,43,51 Kenny found a poorer relationship using Vα(r) (r2 = 0.928, s = 0.196) with roughly the same number of studied compounds, but he selected a more heterogeneous chemical data set.23 In a previous work,50 we also already satisfyingly used the Vα(r) descriptor for H-bond acidity prediction of fluorohydrins. Actually, these compounds are also hydroxyl HBDs that are likely to belong to the data set studied in this work. Indeed, including nine c-hexanols, the regression coefficient and the standard deviation are equivalent but the F-test is now significantly improved (1930−2142, respectively) with 43 hydroxyl HBDs (eq 9, Figure 4B). A tenth c-hexanol has not been included because it deviates significantly from the pKAHY− Vα(r) regression line, probably due to its very low H-bond acidity and its inaccurate experimental and/or theoretical determination. Eventually, the excellent correlations obtained between experimental data in CCl4 and theoretical electrostatic parameters in the gas phase justify the choice to carry out all calculations in the isolated state, the specific solute−solvent interactions being negligible and/or homogeneous in the studied series.

determined. In this case, with a prior calibration between the two CCl4 and CH 2Cl2 solvents, a conversion of the experimental KCH2Cl2 values into secondary KCCl4 data can be achieved. Hence, one-third of the sample found in Table 1 has been studied in CH2Cl2 (Table 2) leading to the calibration line Table 2. HB Acidity Equilibrium Constants, log KCH2Cl2, Measured in Dichloromethane Solution 5 18 19 25 26 27 28 30 31 32 33 34

compounds

log KCH2Cl2

4-fluorophenol 1,1,1,3,3,3-hexafluoroisopropanol 2,2,2-trifluoroethanol testosterone androstanolone allyl alcohol ethynyl-c-pentanol borneol c-pentanol mifepristone c-hexanol 2-butanol

1.55 2.19 1.11 0.12 0.04 0.25 0.23 0.02 0.02 0.06 −0.04 −0.06

pKAHY = 52.16Vα(r ) − 15.94 n = 43, r 2 = 0.9812, s = 0.11, F = 2142

If the electrostatic descriptors appear to depict accurately the H-bond acidity evolution, the partial charge parameters qH(MK) and qH(CHelpG) yield on the contrary very poor regression coefficients when correlated with pKAHY data, r2 = 0.204 and 0.402, respectively, even if compounds 14 and 17 are excluded. Galabov and colleagues already emphasized, for a series of various CH, OH, and NH HBDs,30 that the partial atomic charges located on the hydrogen atom and evaluated through MK and CHelpG methods indeed do not appear as appropriate descriptors of H-bond acidity. Even considering such a homogeneous family than hydroxyl HBDs in this work, these two theoretical parameters are definitely not appropriate to H-bond acidity estimation. Influence of Intramolecular Interactions on H-Bond Acidity. As mentioned above, and already emphasized for a series of phenols substituted in the ortho-position by various HBA substituents,52 the potential intramolecular interaction in a few compounds can influence significantly their HBD behavior. Compounds 14 and 17 have been identified as almost systematically deviating from the relationships established with pKAHY (Figure 1, 2 and 4), whereas compounds 28 and 32 only deviate from the pKAHY vs ΔνOH plot (Figure 1). The favored conformers of 18, 19, 21, and 22, are likely to show an intramolecular interaction with either one fluorine or chlorine atom, but all these compounds obey the previous relationships. Remarkably, the AIM analyses reveal that a bond critical point (BCP) is indeed found between the Cl and H

Figure 3. pKAHY−log KCH2Cl2 relationship established for a series of 12 hydroxyl HBDs.

(8) and Figure 3. The result confirms the possibility of measuring data in CH2Cl2 before their conversion to values related to the CCl4 solvent. Therefore, this experimental methodology appears useful for secondary pKAHY data estimation, as well as the ΔνOH measurements used above. pKAHY = 1.095 log K CH2Cl 2 + 0.701 n = 12, r 2 = 0.9916, s = 0.08

(9)

(8)

2. Quantum Chemistry Calculations. Selection of Descriptors of H-Bond Acidity. Theoretical investigations have been carried out to rationalize and complete the experimental results. The calculated electrostatic potential descriptors, Vα(r), VS,max, and EPNUC, and the H atomic partial charges, qH(MK) and qH(CHelpG) are reported in Table 3. Good relationships are established between the experimental H-bond acidity parameter pKAHY and the electrostatic potential descriptors, as illustrated by the statistics shown in Table 4. 13188



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Table 3. Theoretical Descriptors of Hydrogen-Bond Acidity Calculated at the MPWB1K/6-31+G(d,p) Level Vα(r)a

compound

a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

3,4,5-trichlorophenol 3,5-dichlorophenol 4-bromophenol 4-chlorophenol 4-fluorophenol 1-naphthol 3,5-dimethoxyphenol 3-isopropylphenol 4-methoxyphenol phenol 3-tert-butylphenol 4-methylphenol 4-tert-butylphenol 2,3,4,5,6-pentachlorophenol 3,5-di-isopropylphenol 3,4,5-trimethylphenol 2,4-dichlorophenol

18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

1,1,1,3,3,3-hexafluoroisopropanol 2,2,2-trifluoroethanol 3-nitrobenzyl alcohol 2,2,2-trichloroethanol 2,2-dichloroethanol 3-methoxybenzyl alcohol benzyl alcohol testosterone androstanolone allyl alcohol ethynyl-c-pentanol ethanol borneol c-pentanol mifepristone c-hexanol 2-butanol

35 36

acetone oxime c-hexanone oxime

Vs,maxa

Phenols 0.1066 0.1029 0.0959 0.0954 0.0935 0.0896 0.0901 0.0867 0.0861 0.0887 0.0865 0.0864 0.0864 0.0868 0.0813 0.0833 0.0739 Aliphatic Alcohols 0.3644 0.0991 0.3457 0.0865 0.3425 0.0866 0.3410 0.0789 0.3347 0.0736 0.3235 0.0703 0.3280 0.0756 0.3262 0.0740 0.3236 0.0708 0.3235 0.0705 0.3239 0.0687 0.3207 0.0713 0.3204 0.0696 0.3193 0.0688 0.3218 0.0665 0.3179 0.0673 0.3187 0.0679 Oximes 0.3288 0.0741 0.3270 0.0730 0.3695 0.3651 0.3568 0.3563 0.3535 0.3511 0.3436 0.3436 0.3439 0.3477 0.3451 0.3448 0.3448 0.3634 0.3383 0.3410 0.3482

EPNUCa

qH(MK)a

qH(CHelpG)a

−0.9431 −0.9480 −0.9584 −0.9591 −0.9627 −0.9642 −0.9718 −0.9715 −0.9738 −0.9688 −0.9720 −0.9723 −0.9722 −0.9326 −0.9809 −0.9753 −0.9520

0.4499 0.4498 0.4503 0.4455 0.4417 0.4458 0.4524 0.4437 0.4355 0.4373 0.4416 0.4420 0.4453 0.4293 0.4433 0.4248 0.4116

0.4477 0.4463 0.4390 0.4396 0.4359 0.4372 0.4454 0.4405 0.4347 0.4398 0.4416 0.4329 0.4378 0.4173 0.4382 0.4290 0.4093

−0.9426 −0.9693 −0.9783 −0.9713 −0.9787 −0.9986 −0.9949 −0.9980 −1.0008 −0.9995 −0.9963 −1.0051 −1.0049 −1.0062 −0.9976 −1.0074 −1.0068

0.4435 0.4262 0.4336 0.4210 0.4177 0.4189 0.4304 0.4262 0.4260 0.4254 0.4279 0.4260 0.4224 0.4271 0.4498 0.4263 0.4211

0.4398 0.4194 0.4112 0.4109 0.4040 0.3890 0.4115 0.4239 0.4215 0.4100 0.4100 0.4199 0.4165 0.4210 0.4169 0.4197 0.4168

−0.9900 −0.9922

0.4742 0.4574

0.4492 0.4443

In a.u.

Table 4. Determination Coefficients (r2) and Standard Deviations (s) for the Regression of pKAHY on Theoretical Descriptors r2/s

n

Vα(r)

Vs,max

EPNUC

qH(MK)

qH(CHelpG)

whole sample without o-chlorophenols

36 34

0.935/0.21 0.984/0.11

0.953/0.17 0.971/0.14

0.827/0.33 0.963/0.16

0.171/0.73 0.204/0.74

0.363/0.64 0.402/0.64

shorter, 82.2% and 84.2% respectively, than the sum of the corresponding van der Waals radii (rCl, 1.75 Å;54 rH, 1.10 Å55). Even if the interaction is not strong enough to be classified as an intramolecular H-bond and to deplete the H-bond acidity of compounds 18, 19, 21, 22, 28, and 32, their preferred conformations nevertheless correspond to such geometries, and the H···X distances are spread over 93−97% of the sum of the X and H atoms van der Waals radii.54 A similar behavior was observed previously for fluorohydrins showing an OH···F intramolecular interaction, strong enough to stabilize chelated conformations and reduce their H-bond acidity but too weak to be identified as an intramolecular hydrogen bond.50 The 1,3coaxial fluorohydrin was the only derivative found with a BCP

atoms in 14 and 17 (ρ = 0.0198 and 0.0175 e, respectively), no BCP being found for any of the other compounds. The weak electron density values found at these two BCPs are typical of an H-bond interaction,53 and a NBO analysis also confirms that a significant charge transfer occurs (E(2)n→σ* values calculated through second-order perturbation theory of 21.8 and 17.3 kJ mol−1, respectively) from the chlorine lone pair to the antibonding σ*OH orbital. The larger deviations from the regression lines found for 14 by comparison with 17 are in agreement with its stronger intramolecular H-bond interaction identified through the AIM and NBO analyses. Moreover, the H···Cl distance is shorter in 14 (2.343 Å) than in 17 (2.399 Å), both being significantly 13189



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carried out for compounds 37−39. Even if these compounds can give an intramolecular interaction between their hydroxyl group and either a fluorine or a chlorine atom, no BCP were found during the AIM analyses, suggesting that this interaction is weak and hence that they obey the pKAHY−Vα(r) relationship (9), unlike 14 and 17. Three experimental or theoretical parameters have thus been used to propose secondary pKAHY values for these alcohols (Table 5), using the established calibration lines (7)−(9). We find a quite good agreement between the “experimental” and “theoretical” secondary pKAHY values, the main difference being 0.21 log units for 2fluoroethanol, whereas the standard deviation of each regression line is 0.13, 0.08, and 0.11, respectively. Moreover, we find for chlorine as well as for fluorine derivatives an increase of H-bond acidity upon halogenation that is very weak from ethanol to monohalogenoethanol, and much more important from mono- to dihalogenoethanol. This is in phase with our recent findings on the influence of fluorine on the Hbond acidity of c-hexanol derivatives,50 despite the absence of any BCP. H-bond Acidity Prediction of Steroid Derivatives. In the experimental sample, a few steroid derivatives have been included, showing a hydroxyl group on their c-pentyl moiety. We selected derivatives with a more or less extended conjugated system with the C3O carbonyl group (Figure 5), to establish whether it significantly modifies the H-bond acidity of the nonconjugated c-pentanol moiety. Among the eight selected derivatives, only three of them (25, 26, and 32) were actually soluble enough in CCl4 to measure their pKAHY value (Table 1). A secondary pKAHY value was nevertheless reachable (Table 5) for trenbolone 41 and ethisterone 42 in CH2Cl2, whereas boldenone 40 was not soluble in CH2Cl2. Consequently, the theoretical calculations were the only useful method to predict its H-bond acidity. Likewise, dehydronandrolone 43 has not been studied experimentally in this work due to supply difficulties, and the electrostatic Vα(r) value is therefore used for its pKAHY estimation. In the series 26, 25, 43, 41, the increase of conjugation on the carbonyl moiety brings just a slight but systematic increase of H-bond acidity to the hydroxyl group, unless it is itself conjugated to the π-system. Eventually, dehydrotrenbolone 44 is a virtual structure in which the hydroxyl moiety is conjugated to the carbonyl group thanks to the π-system distributed along the steroid structure. Although the energetic increase was not higher than 2 kJ mol−1 from 25 to 41, the H-bond acidity of 44 is 9 kJ mol−1 stronger than 41, the conjugation conferring an H-bond ability (pKAHY = 2.84) almost as strong as the more acidic phenols or HFIP (18).

Figure 4. (A) pKAHY−Vα(r) relationship established for a series of 34 hydroxyl HBDs, showing the deviations of intramolecularly H-bonded chlorophenols, 14 and 17. (B) Extension of the data set to fluorohydrins previously studied (in pink), with the exception (in red) of the strongly chelated 3-fluoro-4-tert-butylcyclohexan-1-ol.50

between the F and H atoms and a charge transfer between the fluorine lone pair to the antibonding σ*OH orbital, both typical of a H-bond interaction. As well as for 14 and 17, this compound does not obey to the pKAHY−Vα(r) regression line, but the rationalization of the upward deviation remains to be understood. 3. Secondary pKAHY Values. H-bond Acidity Prediction of Halogenoethanols. 2,2-Difluoroethanol (37) was not soluble in CCl4, and its equilibrium constant was then measured in CH2Cl2. 2-Fluoroethanol (38) and 2-chloroethanol (39) were judged to be too toxic to carry out a complete equilibrium constant determination, and we thus only measure their frequency shift value ΔνOH. Theoretical calculations were also

Table 5. Secondary pKAHY Values Estimated for Toxic or Insoluble Compounds in CCl4 37 38 39 40 41 42 43 44

compound

log K(CH2Cl2)

2,2-difluoroethanol 2-fluoroethanol 2-chloroethanol boldenone trenbolone ethisterone dehydronandrolone dehydrotrenbolone

0.88

ΔνOH

pKAHYa

Vα(r)

pKAHYb

pKAHYc

205 191

1.66 1.00 0.88

0.3358 0.3208 0.3230 0.3279 0.3323 0.3285 0.3293 0.3601

1.57 0.79 0.91 1.16 1.39 1.19 1.23 2.84

1.62 0.90 0.90 1.16 1.23 1.05 1.23 2.84

0.33 0.18

1.06 0.90

a

Secondary pKAHY value calculated through either eq 7 or 8. bSecondary pKAHY value calculated through eq 9. cMean pKAHY value from both predictions. 13190



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been carried out for the β-sheets and α-helix structures. These two latter were built from the Molden software,57 and the geometries of the Ser, Thr, or Tyr lateral chains were optimized, the β-sheet or α-helix arrangements being frozen. The pKAHY H-bond acidity of the corresponding structures was then estimated through the calculation of Vα(r) using eq 9 established above. By comparison with 4-methylphenol 12 (pKAHY = 2.05), the single isolated structure does not seem to have a significant influence on the H-bond acidity of the Tyr hydroxyl group (pKAHY = 2.04). A slight increase is estimated when the residue is involved in a β-sheet arrangement, the pKAHY value estimated, of 2.11, showing a slightly stronger Hbond acidity, even higher when it is located in a α-helix structure (pKAHY = 2.23). The behavior of the Ser and Thr aliphatic hydroxyl moieties is different because a strong increase of H-bond acidity is calculated in the single isolated motif (pKAHY = 1.84 and 1.70) by comparison with ethanol 29 (pKAHY = 0.75), whereas a lowering is on the contrary observed when the residues belong to β-sheet and α-helix structures. In the single isolated structures, the presence of an intramolecular NH···OH (2.050 and 2.068 Å) interaction suggests a significant cooperative effect of the NH amide moiety on the OH H-bond acidity, justifying the H-bond acidity increase. Conversely, the β-sheet and α-helix structures do not show any intramolecular interaction rationalizing the observed H-bond acidity decrease. Even if they remain weaker HBDs, the aliphatic hydroxyl groups therefore appear to be competitive toward the aromatic ones within these structural motifs, whereas aliphatic alcohols are very poor HBDs by comparison with phenols. The study in the crystalline state of hydroxylic amino acids involved in molecular interactions (Figure 7) with an amide

Figure 5. Chemical structures of the hydroxylic steroid derivatives considered in this work.

H-Bond Acidity Prediction of Hydroxylic Amino Acids. Recently, Lapointe et al. have assessed the effect of amino acid substitution at the central position of a peptide on the stability of the H-bond network in α-helix models.56 Conversely, to the best of our knowledge, the influence of the immediate surroundings on the H-bond properties of amino acids has not been studied. In this work, we investigate this issue for hydroxylic amino acids. Indeed, because their OH group is frequently involved in molecular interactions with the protein surroundings, it appears of particular interest to estimate their H-bond ability in various molecular environments. The serine, threonine, and tyrosine residues have therefore been simulated as single isolated residues and inserted in β-sheets and α-helix arrangements to investigate the influence of the corresponding environments on the OH groups H-bond ability. The N- and C-terminal ends of the studied structures were respectively capped with acetyl (CH 3 CO−) and N-methylamino (−NHCH3) groups to preserve the planar geometrical features of the peptide bonds. The resulting structures are shown in Figure 6. The single isolated structures have been fully optimized, whereas only a partial geometry optimization has

Figure 7. Definition of hydroxylic amino acid-like structures (on the example of Thr) involved in H-bond interaction with an amide motif, investigated in the CSD.

moiety corroborates these trends. Crystallographic data were obtained from the Cambridge Structural Database (CSD version 5.34, November 2012),58 which contains 596 810 crystal structures. To restrict the searches to better quality CSD entries, the following general search filters were also chosen from the ConQuest59 search menu: 3D coordinates determined, not disordered, no errors, not polymeric, no ions, and only organics. The structures containing Ser-, Thr-, and Tyrlike structures, as defined in Figure 7, have then been investigated before adding an amide motif involved in a close interaction with the hydroxyl moiety, that is, inter- or intramolecular contacts, showing an O···H distance shorter than the sum of their respective van der Waals radii (rO, 1.52 Å;54 rH, 1.10 Å55). We selected the amide group as HBA because (i) it is necessarily present in the structures studied, (ii) it leads to a homogeneous accepting group to investigate the Hbond donor ability of the hydroxyl group, and (iii) it corresponds to the acceptor site found in NMP, the experimental HBA studied. As shown in Table 6, we found between 30 and 60 crystalline structures in the CSD involving the defined Ser-, Thr-, and Tyr-like motifs, a significant ratio being in close contact with an amide moiety. Interestingly, the

Figure 6. Structures and predicted H-bond acidity of the hydroxylic amino acids involved in single isolated structures, β-sheet, and α-helix arrangements. 13191



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ACKNOWLEDGMENTS This work was granted access to the HPC resources of [CCRT/CINES/IDRIS] under the allocation c2012085117 made by GENCI (Grand Equipement National de Calcul Intensif). We thank the CCIPL (Centre de Calcul Intensif des Pays de la Loire) for grants of computer time.

Table 6. Number N of Crystalline Structures Containing a Ser-, Thr-, or Tyr-Like Structure, Number n of Such Structures in Interaction with an Amide Moiety with the Intermolecular dH···O Distance and the θOH···O Directionality structure

N

n

n/N (%)

dH···O (Å)

θOH···O (deg)

Ser Thr Tyr

52 30 60

37 17 23

71 57 38

1.840 (46) 1.946 (31) 1.762 (26)

156° 144° 160°

■

■

CONCLUSION Experimental H-bond donating capacities of hydroxylic donors have been evaluated by FTIR spectroscopy toward Nmethylpyrrolidinone in CCl4 solution, allowing the definition of the pKAHY scale, and in a few cases in CH2Cl2 solution. At the MPWB1K/6-31+G(d,p) level, density functional theory calculations carried out in the gas phase appear to satisfactorily describe the H-bond donor ability within the hydroxylic family, provided that an electrostatic descriptor is selected. The Kenny descriptor, Vα(r), is found to give the best statistics and is selected for the prediction of secondary pKAHY values for experimentally unreachable compounds, e.g., steroid derivatives and simplified protein environments for hydroxylic amino acids. The different relationships established with pKAHY are generally not obeyed by compounds showing potential intramolecular interactions, but the Vα(r) parameter is the most robust. Indeed, the only compounds that are not properly described are those in which the hydroxyl group is involved in an intramolecular H-bond (identified by a bond critical point). The behavior of previously studied fluorohydrins is in excellent agreement with the more extended sample studied in this work. An evaluation of the H-bond ability of hydroxylic amino acids suggests that Ser- and Thr-like structures are much more acidic than aliphatic alcohols whereas no significant difference is found for Tyr-like structures. In this context, the hydroxyl moieties of Ser and Thr should hence be considered as significant H-bond donors. ASSOCIATED CONTENT

S Supporting Information *

Secondary pKAHY values of hydroxyl compounds calculated from the log KHA data. This material is available free of charge via the Internet at http://pubs.acs.org.

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OH···O interaction distances decrease in the order Thr > Ser > Tyr, whereas the directionality increases in the same order, strongly suggesting an H-bond acidity in the order Thr < Ser < Tyr. This trend is indeed in good agreement with the predicted hydroxyl H-bond acidity calculated from their electrostatic potential values.

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AUTHOR INFORMATION

Corresponding Authors

*J. Graton: phone, (+33) 276645168; fax, (+33) 251125402, email, [email protected]. *J. Y. Le Questel: phone, (+33) 251125563; fax, (+33) 251125402, e-mail, [email protected]. Notes

The authors declare no competing financial interest. 13192



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Hydrogen-Bond Acidity of OH Groups in Various Molecular

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