The pKBHX database: a collection of complexation constants and spectroscopic shifts measuring the hydrogen-bond basicity of organic species towards a reference hydrogen-bond donor.

Group “Hydrogen bonding and neuroactive molecules” CEISAM UMR CNRS 6230

Faculté des Sciences et des Techniques 2 rue de la Houssinière – BP 92208

44322 NANTES Cedex 3 FRANCE

(formerly Laboratoire de Spectrochimie et Modélisation, UPRES EA 1149, Université de Nantes) Contacts: Licensing informations: Jean-Yves.Le-Questel@univ-nantes.fr Support : Eric.Renault@univ-nantes.fr (database) Jerome.graton@univ-nantes.fr (chemistry)

1. Definitions:

Hydrogen bond Hydrogen-bond basicity Complexation constant Spectroscopic shift pKBHX database

2. Description of the fields HBA data

Structure of HBA Formula HBA Name pKBHX Registry Number Molecular weight InChI

Thermodynamic data Atom Function and Subfunction pKBHX pKBHX comment:

approx. secondary stat. corr.

Kt Spectroscopic data

HBD Solvent ∆ν (delta nu) ∆ν comment

Reference 3. Selected entries:

s-Triazine Methyl nicotinate 1,10-Phenanthroline Tetramethylguanidine Fluorocyclohexane Iodocyclohexane Progesterone Nicotine

Cotinine Tetrabutylammonium chloride

1. Definitions:

Hydrogen bond Water, alcohols, phenols, hydrogen halides, carboxylic acids, primary and secondary amines and amides,

thiols, 1-alkynes, polyhalogenated alkanes, etc. constitute a special class of Lewis acids .They all contain

an XH group in which the hydrogen atom is bonded to an electronegative atom X and bears a partial

positive charge. The hydrogen has an electrostatic attraction to high electron density regions, primarily

the lone pairs of Lewis bases B, and a hydrogen bond (HB) X-H…B is formed. In addition to this

electrostatic interaction there is a charge transfer from the base to the antibonding orbital σ* of the X-H

sigma bond. The respective contributions of electrostatic forces and charge transfer are still a matter of

debate. In any case, the hydrogen bonding interaction can be considered as Lewis acid-base in nature.

The hydrogen-bond donor (HBD) XH is the electron acceptor and the hydrogen-bond acceptor (HBA) B

is the electron donor.

Hydrogen-bond basicity The reaction

X-H + B X-H…B

XH + B XH B of formation of a hydrogen bond between the molecules XH and B, can be used for the construction of a

Lewis basicity scale. This scale may be created by measuring the equilibrium constant K of this reaction

for a series of bases B under the same conditions: physical state (gas or solution in a given solvent),

temperature and pressure. Such a scale, transformed as log K or ∆G, is named hydrogen- bond basicity

scale.

Complexation constant On account of the importance of the hydrogen bond in physical, chemical and biological sciences, a

great number of hydrogen-bond complexation constants have been measured. The first text by Pimentel

and McClellan (1960) devoted entirely to hydrogen bonding contains a table of nearly 300 entries of

thermodynamic data for HB formation. Another book by Joesten and Schaad (1974) gives an appendix

of thermodynamic data from 1960 to 1973 containing nearly 2000 entries. Within this accumulation of

inhomogeneous measurements, only those of a collaborative work between the groups of Taft, Arnett,

and Schleyer focused upon building a hydrogen-bond basicity scale. Subsequently, the groups of

Abraham and Laurence worked towards the same objective.

Spectroscopic shift The formation of a hydrogen-bonded complex X-H…B induces a spectacular shift to lower

wavenumbers of the stretching vibration of the X-H bond. This shift is defined as

∆ν(XH) / cm-1 = ν(free XH) – ν(hydrogen-bonded XH)

There exists accurate family-dependent relationships between thermodynamics of complexing and

spectroscopic shifts. These relationships are useful (i) for the study of steric effects on the hydrogen-

bond formation, (ii) for detecting three-centered hydrogen bonds, and (iii) for estimating the individual

complexation constants of bases with multiple HBA sites.

pKBHX database In order to gather in electronic format the homogeneous, numerous and diversified published and

unpublished results of our group, we have created the so-called pKBHX database with the software MDL

ISIS™/Base.

This database contains presently ca. 1200 entries, each of which refers to a given chemical species

(molecule or ion pair) and contains a number of fields which are described below.

2. Description of the fields The fields of the pKBHX database are summarized in table 1. Figure 1 shows the display of the

corresponding interface.

Table 1. Hierarchical structure of the pKBHX database (parent fields between brackets, type of child fields between parenthesis, and external name in italics)

<Root>

ID (integer) pKBHX_Registry_Number

HBA_chemical_structure (structure) HBA_structure

*fmla_HBA_chemical_structure (formula)

*mol.weight_HBA_chemical_struc (real)

Inchi (variable text) InChI

<data_name_HBA> HBA_name

(variable text)

<Data_pKBHX> atom

(variable text)

function (variable text)

subfunction (variable text)

pKBHX (real)

pKBHX_comment (variable text)

pKBHX_reference (variable text)

<data_HBD> HBD_name

(variable text)

solvent (structure)

delta_nu (real)

delta_nu_comment (variable text)

delta_nu_reference (variable text)

Kt (real)

Kt_comment (variable text)

Kt_reference (variable text)

Figure 1.Display of an entry of the pKBHX database

HBA data Structure of HBA

2D structure of the hydrogen-bond acceptor (HBA), drawn with MDL ISIS™/Draw.

Formula

The carbon and the hydrogen atoms are positioned in the first and second places followed by

heteroatoms in alphabetical order (e.g. C6H10F3NO).

HBA Name

Chemical name of the HBA, either systematic and/or common. The systematic IUPAC name is

determined from ACD/Name systematic nomenclature software. The common name corresponds to that

found in most catalogs of chemical compounds.

pKBHX Registry Number

A unique numerical identifier designating a given HBA. There are 1164 such numbers (that is entries) in

the version 08.05.

Molecular weight

Dimensionless. Related to the molar mass by: molar mass = molecular weight x 1 g/mol.

InChI

The IUPAC International Chemical Identifier (InChITM) is a non-proprietary identifier for chemical

species, representing the 2D chemical structure as a unique string of characters.

Thermodynamic data Atom

Atomic site of the HBA where the HBD is attached. The occurrence n of the atomic sites is given in

table 2.

Table 2. Occurrence of HBA sites in the pKBHX database. Group 14 n Group 15 n Group 16 n Group 17 n Carbon 119 Oxygen 618 Nitrogen 513 Fluorine 10 Sulfur 96 Phosphorus 1 Chlorine 36 Selenium 4 Arsenic 2 Bromine 17 Tellurium 1 Antimony 1 Iodine 15

Function and Subfunction

The same atomic HBA site can be engaged in various organic functional groups. For example, nitrogen

bases can be nitriles, imines, amines etc. The subfunction describes more precisely a family of functional

groups. For example a carbonyl group may correspond to aldehydes, ketones, esters, amides, carbonates,

ureas etc. The occurrence n of functions and subfunctions in the pKBHX database is given in table 3.

Table 3. Functions and subfunctions corresponding to atomic HBA sites.

Atom Function Subfunction n Atom Function Subfunction n antimony stibine - 1 oxygen carbonyl ketone 125 arsenic arsine - 2 oxygen carbonyl lactam 4 bromine - - 1 oxygen carbonyl lactone 7 bromine bromoalkane - 17 oxygen carbonyl thiocarbamate 1 carbon alkene - 10 oxygen carbonyl urea 8 carbon alkyne - 9 oxygen ether - 95 carbon arene - 97 oxygen nitro - 5 carbon heteroarene pyridine 2 oxygen nitro nitramidate 2 carbon heteroarene - 1 oxygen nitro nitramide 1 chlorine - - 2 oxygen nitro nitroalkane 5 chlorine chloroalkane - 36 oxygen nitro nitroalkene 5 fluorine fluoroalkane - 10 oxygen nitro nitroaromatic 9 iodine - - 2 oxygen nitroso - 2 iodine iodoalkane - 15 oxygen nitroso nitrosamine 3 nitrogen - - 4 oxygen peroxide - 6 nitrogen amidine - 24 oxygen phenol - 5 nitrogen amidine acetamidine 11 oxygen phosphoryl - 15 nitrogen amidine benzamidine 12 oxygen phosphoryl phosphate 8 nitrogen amidine formamidine 35 oxygen phosphoryl phosphinate 7 nitrogen amidine guanidine 4 oxygen phosphoryl phosphine oxide 11 nitrogen amine - 34 oxygen phosphoryl phosphonate 31 nitrogen amine primary amine 28 oxygen phosphoryl phosphoramide 2 nitrogen amine secondary amine 39 oxygen pyridine N-oxide - 8 nitrogen amine tertiary amine 56 oxygen seleninyl selenoxide 2 nitrogen diazene - 2 oxygen siloxane - 1 nitrogen heteroarene - 19 oxygen sulfinyl - 1 nitrogen heteroarene imidazole 7 oxygen sulfinyl sulfinamide 3 nitrogen heteroarene isoxazole 2 oxygen sulfinyl sulfite 5 nitrogen heteroarene oxazole 4 oxygen sulfinyl sulfoxide 14 nitrogen heteroarene phenanthroline 7 oxygen sulfonyl - 6 nitrogen heteroarene pyrazole 1 oxygen sulfonyl sulfate 2 nitrogen heteroarene pyridine 91 oxygen sulfonyl sulfonamidate 4 nitrogen heteroarene pyrimidine 2 oxygen sulfonyl sulfonamide 6 nitrogen heteroarene pyrrole 3 oxygen sulfonyl sulfonate 2 nitrogen heteroarene thiazole 2 oxygen sulfonyl sulfone 8 nitrogen imine - 14 phosphorus nitro nitroaromatic 9 nitrogen imine oxime 2 selenium phosphine - 1 nitrogen nitrile - 91 selenium selenide - 2 nitrogen nitrile cyanamidate 1 selenium selenophosphoryl phosphine selenide 1 nitrogen nitrile cyanamide 7 sulfur disulfide - 2 nitrogen nitrile cyanate 1 sulfur isothiocyanate - 2 nitrogen nitrile thiocyanate 1 sulfur selenophosphoryl selenophosphate 1 nitrogen pyridine 12 sulfur sulfide - 33 oxygen - - 6 sulfur thiocarbonyl - 6 oxygen alcohol - 21 sulfur thiocarbonyl dithiocarbamate 1 oxygen amine N-oxide - 4 sulfur thiocarbonyl thioamide 27 oxygen arsine N-oxide - 2 sulfur thiocarbonyl thiocarbamate 1 oxygen carbonyl - 6 sulfur thiocarbonyl thioketone 1 oxygen carbonyl acid anhydrid 2 sulfur thiocarbonyl thiourea 6 oxygen carbonyl aldehyde 9 sulfur thiocarbonyl trithiocarbonate 1 oxygen carbonyl amide 64 sulfur thiol - 6 oxygen carbonyl carbamate 8 sulfur thiophosphoryl - 2 oxygen carbonyl carbonate 5 sulfur thiophosphoryl phosphine sulfide 5 oxygen carbonyl carboxamidate 10 sulfur thiophosphoryl thiophosphate 2 oxygen carbonyl ester 60 sulphur thiophosphoryl thiophosphoramide 1 oxygen carbonyl imide 8 tellurium telluride - 1

pKBHX

Let Kc be the equilibrium constant for the hydrogen bonding of a variety of Lewis bases with the

reference hydrogen-bond donor 4-fluorophenol in CCl4 at 25°C.

F OH

+ B F OH

B4-fluorophenolhydrogen-bond donor

HBD

Lewis basehydrogen-bond acceptor

HBAhydrogen-bonded complex

C

Kc / L mol-1 = [C] / [HBD] [HBA]

where [ ] stands for the equilibrium molar concentration. Since Kc values vary over many orders of

magnitude, it is convenient to use a logarithmic scale.

The symbol pKHB proposed by Taft, where the subscript HB stands for “Hydrogen Bond”, does not

specify if pKHB is a hydrogen-bond basicity or acidity scale. The ambiguity can be cleared up by

returning to a symbol similar to the well-accepted symbol pKBH+, which measures the basicity towards

H+ and is defined as the antilog of the dissociation constant of the species BH+. We propose to call

pKBHX the scale measuring the basicity towards HX (where X stands for 4-FC6H4O) and to define pKBHX

as the antilog of the dissociation constant, 1/Kc, of the complex BHX (B…HX).

pKBHX = - log10 [1 / (Kc / 1 L mol-1)] = log10 (Kc / 1 L mol-1)

With these definitions, the strongest Brønsted base and the best hydrogen-bond base have respectively

the largest pKBH+ and pKBHX values.

The Kc values have been obtained by measuring the equilibrium concentration of 4-fluorophenol from

the absorbance of the O-H infrared band at 3614 cm-1 by means of a FTIR spectrometer. From separate

determinations by various operators on different spectrometers under varied experimental conditions,

pKBHX values are believed to be accurate within ±0.02- ±0.05. This accuracy is to be compared to the

broadness of the scale from ca -1 for very weak hydrogen-bond bases to ca +6 for very strong hydrogen-

bond bases.

Because most species are very dilute and neutral, Kc is assumed to be close to the thermodynamic

equilibrium constant relative to activities. So the pKBHX scale can be converted to a Gibbs energy scale

through the equations o

BHX∆ = - ln10 pG RT K

o -1298 BHX∆ /kJ mol = -5.708 pG K

The version 08.05 of the database contains 1388 pKBHX values.

pKBHX comment:

approx.

Correspond to pKBHX values of lower accuracy than ±0.05.

secondary

It is highly desirable to determine the pKBHX values experimentally and these are referred to as primary

values. Secondary values correspond to compounds not accessible to direct FTIR measurements in CCl4,

either because sparingly soluble, too strongly interacting with 4-fluorophenol, measured with another

reference HBD (e.g. phenol) or measured in another solvent (e.g. CH2Cl2). These values are calculated

through linear free energy relationships or correlations with OH infrared shifts, sigma substituent

constants and quantum chemical descriptors of hydrogen-bond basicity. The accuracy is generally lower

for secondary values than for primary values.

stat. corr.

In the case of polybases with n equivalent (quasi-equivalent) atomic sites, a – log n statistical correction

is applied to put the pKBHX value on a per atom basis. For example the total complexation constant of s-

triazine

N

N

N

is 6.3 L mol-1. The statistically corrected quantity log 6.3 - log 3 = 0.32 refers to the hydrogen-bond

basicity per nitrogen atom and can be used for comparison with monobasic pyridines.

Kt

With the conditions used for measuring by FTIR spectrometry the complexation constants of

polyfunctional molecules containing n HBA sites, n 1:1 complexes are formed through equilibria of

individual constants Kc(i). With this method only the sum, Kc(t), of the individual constants can be

usually measured

c ci

(t) = (i)K K∑

A number of methods have been proposed for separating Kc(t) into individual Kc(i)’s. For example the

total equilibrium constant for the hydrogen bonding of 4-fluorophenol to cotinine,

N

N

Me

O

Kc(t) = 197 ± 14 L mol-1 has been separated into the constants for the carbonyl oxygen,

Kc(O) = 145 ± 10 L mol-1, and for the pyridine nitrogen, Kc(N) = 42 ± 12 L mol-1. Thus, on the pKBHX

scale, the hydrogen-bond basicity of cotinine is described by two values, pKBHX = 2.16 and

pKBHX = 1.62, respectively for the oxygen and nitrogen sites.

Spectroscopic data HBD

Primary pKBHX and Kt values refer always to 4-fluorophenol. ∆ν values may refer either to

4-fluorophenol and/or methanol.

Solvent

CCl4 for most compounds, C2Cl4 for a number of amines, c-C6H12 for phosphines, stibines, tellurides etc

(reacting with CCl4), and CH2Cl2 for sparingly soluble compounds.

∆ν (delta nu)

The shift to lower wavenumbers of the stretching vibration of the O-H bond of 4-fluorophenol at

3614 cm-1 in CCl4 is defined as

∆ν(OH) / cm-1 = ν(free OH) – ν(hydrogen-bonded OH)

409 ∆ν (OH) values are included in the version 08.05 of the database.

Methanol is a more appropriate reference hydrogen-bond donor than 4-fluorophenol for establishing a

spectroscopic scale of hydrogen-bond basicity because shifts greater than 500 cm-1 cannot be easily

measured with 4-fluorophenol. So, we advocate a scale based on the shift of the O-H band of methanol

at 3644 cm-1 in CCl4. This shift is defined as

∆ν(OH) / cm-1 = 3644 – ν(OH in CH3OH…B)

The version 08.05 of the pKBHX database contains 790 ∆ν(OH) values for methanol complexes. They

span from ca 3 cm-1 for the very weak chloro base CHCl3 to 488 cm-1 for the very strong oxygen base

Oct3NO. They allow the establishment of many useful pKBHX / ∆ν(OH) family-dependent relationships.

∆ν comment

In the IR spectra of hydrogen-bonded complexes of polyfunctional bases, multiple OH bands are often

observed, indicative of more than one significant HBA site. The comment “O, N or S complexes” means

that ∆ν (OH) values correspond to the hydrogen bonding of the OH group to respectively oxygen,

nitrogen or sulfur site of the HBA.

A number of monofunctional bases, mainly carbonyl bases and ethers, show OH bands of hydrogen-

bonded complexes which are very unsymmetrical, or present a shoulder or are even split. These

dissymmetry, shoulder or doublet may be attributed to different geometries of the complex. So, the

comment “stereoisomeric complexes” is added for these compounds.

Reference There are three kinds of references:

- Published journal articles.

- Ph. D. thesis (M. Helbert, J.Y. Le Questel, A. Chardin, C. Ouvrard, J. Graton, K. Evain, V. Arnaud, in

chronological order) of the University of Nantes.

- Unpublished results of the laboratoire CEISAM (formerly laboratoire de Spectrochimie moléculaire,

then laboratoire de Spectrochimie, then laboratoire de Spectrochimie et Modélisation). These results

have been mostly obtained by the technical staff of the laboratory (F. Besseau, M. Luçon, and A.

Planchat) and by master degree students (J.C. Blot, D. Foucher, M.D. Hardy, A. Locati, E. Marquis, C.

Martin, M. L. Riley, C. Rossignol, M. Safar, and F. Thireau) (in alphabetic order).

3. Selected entries:

s-Triazine

Methyl nicotinate

1,10-Phenanthroline

Tetramethylguanidine

Fluorocyclohexane

Iodocyclohexane

Progesterone

Nicotine

Cotinine

Tetrabutylammonium chloride