Hydrogen bonding plays a fundamental role in many chemical and biological problems, from the study of water’s properties to the binding of base pairs in the DNA double helix. The energy and structural properties of the H-bond are intermediate to those of the classical covalent bond and van der Waals interactions. Conditionally, hydrogen bonding involves energies up to 60 kJ/mole, and bond lengths as short as 0.2 nm.
Approaches for studying hydrogen bonds can be divided into two groups: quantum chemical calculations and empirical methods. The use of ab initio calculations allows the energy and geometric structures of small molecules to be described with an accuracy approaching those of experimental results. However, a similar treatment of large molecules is not yet practical. Here we will be concerned only with empirical methods, exclusively correlation models.
HYBOT includes a correlation model founded on its thermodynamic database (the enthalpies and free energies of H-bond formation). This model estimates the relative proton acceptor and proton donor strengths of compounds in the form of factors using a common H-bond scale. These factors have been used successfully to discover significant relationships between chemical structure and biological activity. Of particular importance is the influence that H-bonding has upon lipophilicity, a physical property that plays an important role in drug transport in biological systems and in drug-receptor binding. Lipophilicity is usually expressed as the logarithm of a compound’s distribution coefficient between n-octanol and water (log P).
Factor calculations based on experimental thermodynamic data
Thermodynamic data form the quantitative basis for the one-centre hydrogen bond model discussed in this section. A complete thermodynamic description of hydrogen bonding involves free energy (D G), enthalpy (D H) and entropy (D S) which are related to each other by the following equation:
D G = D H - TD S (1)
where T is the absolute temperature in degrees Kelvin (° K).
A simple multiplicative expression for estimating H-bond enthalpy was proposed in pioneering works by Sherry and Purcell  and by Iogansen . This approach is based on the constancy and mutual independence of donor and acceptor factors of interacting molecules. In 1982 we proposed [3,4] a common hydrogen bond enthalpy scale based on this multiplicative principle. In this case, the enthalpy of H-bond formation is proportional to the product of the factor value for the H-bond donor (Ed) and that for the H-bond acceptor (Ea):
D H = k1EdEa (2)
where k1 is the proportionality constant. The donor factor (Ed) and the acceptor factor (Ea) are determined for various molecules based on their enthalpies in different combinations with other molecules, and by scaling the results to the system phenol-hexamethylphosphoramide (HMPA) in tetrachloromethane (CCl4) at 298 ° K. In this system the H-bond donor factor (that for phenol) was set as Ed = -2.50, and the H-bond acceptor factor (that for HMPA) set as Ea = 2.50 to cover a practical range of values.
A few years later we proposed [5,6] a similar hydrogen bond free energy scale where free energy of H-bond is calculated on the basis of next equation:
D G = k’1Cd Ca + k’o (3)
where Cd and Ca are respectively the H-bond free energy donor and acceptor factors. The system phenol-HMPA in CCl4 was chosen as the reference standard; the H-bond free energy factors Cd and Ca were set at -2.50 (phenol) and 4.00 (HMPA) respectively.
An analogous method for calculating equilibrium constants (K) for H-bonding was proposed independently by Abraham at al :
log K = k"1a b + k"o (4)
where a is proportional to H-bond acidity and b is proportional to H-bond basicity.
We correlated experimental with calculated values of the enthalpies and free energies for approximately 3000 H-bond complexes using the multiplicative approach. Our results are presented in  and are summarized as follows:
D Hcalc = -0.49(± 0.29) + 0.99(± 0.08)D Hexp (5)
n = 2787 r = 0.970 s = 2.40 F = 44350
where n is the number of data points, r the correlation coefficient, s the standard error of the estimate, and F the variance ratio. The numbers in parentheses are the standard errors of the coefficients.
D Gcalc = -0.07(± 0.12) + 1.04(± 0.08)D Gexp (6)
n = 3301 r = 0.991 s = 1.12 F = 175000
In spite of these excellent correlations, we noted in  that the free energy values of a number of strong H-bond complexes involving nitrogen atoms deviated significantly from those calculated by equation (6).
Some of the obstacles in determining the relative strengths of H-bond donors and acceptors by the thermodynamic approach are: (i) in compounds with multiple polar atoms, identifying those atoms directly participating in H-bond formation, (ii) the difficulty of evaluating weak acceptor centres located near strong ones, (iii) the difficulty of determining the acceptor strengths of compounds with charged groups, and (iv) compounds with poor solubility in nonpolar solvents.
Factor calculations based on experimental log P values
Testa and coworkers [10,11] demonstrated that the distribution coefficient of a solute between octanol and water encodes two main structural contributions: the molecular volume of the solute, and the polar interactions between the solute and the solvent. They showed that the latter appears to consist mainly of the H-bond acceptor capacity of the solute. This was the starting point for a new approach to overcome some of the problems [(i)-(iv)] indicated above.
For this purpose, we elected to study a set of simple organic compounds each containing just one acceptor group. Experimental log P values (octanol-water) were taken from the literature. We used polarizabilities (Pol) as estimates for volumes; the computations were based on a literature method . Free energy acceptor factors, Ca(t), were calculated by the method described in the previous section. The results are summarized in the following equation:
log P = 0.266(± 0.006)Pol - 1.00(± 0.05)Ca(t) (7)
n = 71 r = 0.991 s = 0.18 F = 3829
The excellent statistical results expressed in equation (7) afford an opportunity to estimate log P on the basis of computed values for Pol and Ca(t). The intercept for equation (7) is essentially zero; hence, rearrangement of the terms in equation (7) and substitution of Ca(o) for Ca(t) leads to equation (8). This enables the construction of a new scale of factors.
Ca(o) = 0.266Pol - log P (8)
Ca(t) indicates that the H-bond acceptor factor value is based on the thermodynamic database; Ca(o) indicates that the factor stems from log P (either measured or calculated) and calculated Pol; both pieces of information are readily available. For simple substances containing only one acceptor group, Ca(t) and Ca(o) will be approximate in value. In the case of complex organic compounds, the factor value will be the sum of factor values for each acceptor site in the molecule [S Ca(o)].
Factor calculations based on chemical structures
A HYBOT module is used to determine both donor and acceptor factor values for new molecules, even those with many H-bond centres. The structure of the molecule of interest is explored to find fragments corresponding to known compounds in the H-bond Factor libraries. If a good match is found then the database factor value for that match is used for that portion of subject molecule. If a structural fragment is not found in the database then HYBOT calculates it. An account of the method used to evaluate chemical structural environments has been published .
Examples of successful Application H-bond Descriptors
I. Solubility in water [unpublished data]
log(1/S) = - 0.42(± 0.20) + 0.17(± 0.11)Pol - 0.13(± 0.04)S Ca + 0.08(± 0.06)S Cd
n = 45 r = 0.925 s = 0.42
where Pol is polarizability, S Ca is the sum of all acceptor factor values and S Cd is the sum of all donor factor values.
II. LogP (octanol-water) 
log P = 0.266(± 0.005)Pol - 1.00 (± 0.03)Ca
n = 2781 r = 0.971 s =0.32
1. Caco-2 Permeability (logPerm ) 
logPerm = 0.05(± 0.01)MW - 0.20(± 0.03)S Cad
n = 17 r = 0.883
where S Cad is the sum of absolute Ca and Cd values for all H-bond donor and acceptor atoms in molecule, and MW is molecular weight.
2. Human skin permeability (logKp) of steroid hormones 
logKp = - 4.36(± 0.61) - 0.38(± 0.09)Ca + 0.24(± 0.11)Cd
n = 14 r = 0.961 s = 0.30
3. Human skin permeability (logKp) of phenols 
logKp = -3.39(± 0.59) + 0.71(± 0.21)Cd
n = 17 r = 0.883 s = 0.28
4. Human skin permeability (logKp) of 23 diverse compounds 
logKp = - 2.12(± 0.11) - 0.41(± 0.02)S Ca(t) + 0.40(± 0.04)log P
n = 23 r = 0.977 s = 0.28
5. Human Red Cell Basal Permeability (log BP) of alcohols, water, urea and thiourea 
log BP = -0.70(± 0.64) + 1.08(± 0.16)Cd
n = 10 r = 0.983 s = 0.43
6. Permeability (logPerm) of nonelectrolytes through the cells of the alga Chara ceratophylla 
log Perm = 0.83(± 0.57) + 0.59(± 0.12)Cd
n = 27 r = 0.903 s = 0.49
7. Placental Transfer ratio (logTR) of drugs 
logTR = 0.28(± 0.18) - 0.05(± 0.02)Ca + 0.04(± 0.02)Cd
n = 16 r = 0.910 s = 0.13
IV. Absorption and bioavailability
1. Absorption and intraduodenal bioavailability (log AUCid ) of azole endothelin antagonists 
logAUCid = -4.318(± 1.048) + 0.408(± 0.138)Cd
n = 9 r = 0.935 s = 0.319
V. Biological activities
1. Tadpole narcosis [log(1/C]) 
log(1/C) = 0.49(± 0.20) + 0.23(± 0.02)Pol - 0.42(± 0.05)Ca
n = 85 r = 0.954 s = 0.33
2. Affinities for muscarinic receptor (logKi) by some bicyclic compounds 
logKi = - 4.58(± 0.48) - 0.09(± 0.06)Ca + 1.08(± 0.15)logP + 0.27(± 0.08)HBA5.3Å
n = 27 r = 0.918 s = 0.38
where HBA5.3Å = intensity of interaction of H-bond acceptors at a distance of 5.3 Å
3. Anti-HIV-1 activity (logKi)of porphyrines 
logKi = - 6.56(± 1.44) - 2.24(± 0.11)LUMO + 0.05(± 0.03)HBD11.4Å
n = 13 r = 0.961 s = 0.22
where HBD11.4 Å = intensity of interaction of H-bond donors at a distance of 11.4 Å.
4. Symmetrical cyclicurea HIV protease inhibitors 
-log Ki = 11.55(± 1.80) + 0.10(± 0.02)CLOGP2 - 0.95(± 0.26)CLOGP - 0.78(± 0.31)mv
- 0.008(± 0.002)MW - 0.48(± 0.12)Cd(t)NH + 0.51(± 0.09)Ca(t)N
n = 30 r = 0.895 s = 0.33
where log Ki is the inhibition constant; CLOGP is the calculated log P (MedChem program, Pomona College); mv is 1/100th the molecular volume; Cd(t)NH is the H-bond donating factor for a specific amide function; and Ca(t)N is the H-bond acceptor factor for a specific heteroaromatic nitrogen atom.
5. Anticonvalsive activity (log1/C0) of macrocyclic compounds 
log(1/C0) = 5.12(± 1.11) - 29.9(± 0.64)Ca - 0.20(± 0.14)HBA3.6 Å
+ 0.19(± 0.03)HBA5.3 Å
n = 16 r = 0.908 s = 0.20
where HBA3.6 Å = intensity of interaction of H-bond acceptors at a distance of 3.6 Å, and HBA5.3 Å = intensity of interaction of H-bond acceptors at a distance of 5.3 Å
Chapter 2 Technical Data
All data in HYBOT are contained in two databases: the Hydrogen Bond Thermodynamics Database and the Hydrogen Bonding Factors Database. Each database may to have several libraries. A library is a collection of entries (records) containing information about chemical compounds (the number of entries may be greater than number of chemical structures). Each structure has one or more H-bonding centres
Hydrogen Bond Thermodynamics Database:
Each entry has one hydrogen bonding complex, both acceptor and donor structures, and contains the thermodynamic properties, solvent, temperature and reference.
Number of libraries 1
Total number of entries 13,687
Hydrogen Bonding Factors Database:
Each entry has one chemical structure with the active centre marked, and contains donor factors values (those with a negative values) and/or acceptor factor values (those with a positive values).
Number of libraries 13
Total number of entries 67,710
a values calculated from D G
b values calculated from D G
a values (CH-donors) calculated from D G
Ea factors calculated from D H
Ed factors calculated from D H
Ed factors (CH-donors) calculated from D H
Ca factors calculated from D G
Cd factors calculated from D G
Cd factors (CH-donors) calculated from D G
Ca factors calculated from log P
Ca factors (week centres) calculated from log P
Ca factors calculated from log P (new)
Cd factors calculated from correlation data (new)
These libraries may be combined to form training sets for calculating factors for new chemical structures. Initially, HYBOT supplies some training sets that should be sufficient normal use. The following combinations make up these sets:
ALPHA + BETA
EA + ED
CA + CD + CD_NEW
CA(O) + CD
CA(O) + CD + CD_NEW
CA(O) +CA(O)NEW + CD + CD_NEW
Chapter 3 MOLPRO: HBPlus Menu
The MOLPRO: HBPlus menu offers several options that are needed to calculate Ca, Cd, Ea, Ed, a and/or b factors for compounds. When you select the option MOLPRO: HBPlus in the Tools window you will see MOLPRO: HBPlus menu window:
The following table indicates what these options are and what they do.
MOLPRO: HBPlus option
Allows you to view/edit the hydrogen bond thermodynamics database.
HB Factor database
Allows you to view/edit the hydrogen bonding factor database.
HB factor calculation
Calculates the factors of a new molecule on the basis of experimental thermodynamic data.
Allows you to create a new training set made up of libraries of your choice. This option should be taken only by a user with sufficient knowledge of H-bonding and HYBOT to make judicious choices among the libraries. For most work one of the pre-formed training sets should be satisfactory.
Allows you to enter and to edit factor values that can not be calculated from experimental data.
Descriptors: Libraries selection
Sets list of the files for calculation of the factors for many molecules (using a library).
Allow you to see the results of calculation the descriptors for any molecule.
Calculates the descriptors for a library.
Descriptors: Export to Excel
Exports the calculated descriptors into a spread sheet Microsoft ExcelTM
Descriptors: Export to Text file
Exports the calculated descriptors into a text file.
HB factors: Library selection
Sets list of the files for calculation of the factors for a single molecule and for many molecules (using *.sdf file).
HB factors: Element selection
Sets list of proton acceptors and proton donors for calculation of Ca, Cd, Ea, Ed, a and b factors.
HB factors: Predict
Calculates Ca, Cd, Ea, Ed, a and b factors for a single molecule on the basis of its chemical structure and an appropriate training set.
HB factors: Predict from file
Calculates Ca, Cd, Ea, Ed, a and b factors for many molecules on the basis of their chemical structures as described in the (*.sdf) file format (batch mode) and an appropriate training set.
When you select this option you get the following Information window:
This window contains many data fields and buttons; the following table describes what they contain or do.
information contained or action
Shows the record number of the currently selected library entry.
® , ¬
From the current record in the list, the ® button takes you to the record next; the ¬ button takes you to the record prior.
When checked, allows you to edit data in the database.
+ , -
The + button allow to add new entry to database, the - button allow to delete selected entry.
The Ö button saves the selected entry.
The Æ button terminates the process without any action taken.
Allow to change the size of the window.
Selects a form for the database.
Selects a table for the database.
Free energy of complex formation (kJ/mole).
Enthalpy of complex formation (kJ/mole).
Method of free energy determination.
Method of enthalpy determination.
The difference in chemical shifts between free and associated H-bond donor groups (ppm).
The difference between the stretching frequencies for free and associated H bond donor groups (cm-1).
Type of bridge in complex AH...B, where AH is the proton donor group, and B the proton acceptor atom.
Temperature at which experiment was conducted in oK.
Solvent used in the experimental determination.
Stoichiometry of hydrogen bonding complex.
Number of hydrogen bridges in H-bond complex.
Comments on the reference and data.
Authors of the reference publication.
Name of journal or other reference from which the data were taken.
Year of publication.
Journal number in particular volume.
Pages of reference.
Molecular weight of compound.
Chemical Abstracts Registry Number.
Brutto formula of compound.
Chemical structure of hydrogen bond donor.
Chemical structure of hydrogen bond acceptor.
HB Factor database
When you select this option you get the Open window. Select any *.cdb file and click. You see following Information window:
The following table explains what is contained in the data fields and what the buttons do.
Structure of compound.
Name of compound.
CAS Registry Number.
The value of C-factor, E-factor or Alpha(beta)-factor.
To view active centre (coloured atom) click on Ca factor field. To view next structure use combination Ctrl + ¯ .
HB factor calculation
This option allows you to calculate hydrogen bonding factors (Ca, Cd, Ea, and Ed ) from the experimental hydrogen bond thermodynamics database for one centre in a molecule, and to add this information to a library in the factor database. This process is somewhat complicated, but if you
When you select option HB factor calculation in the MOLPRO: HBPlus menu you see the Factor Calculation window:
The following table explains the actions of the various items on the screen.
Save result in
Selects the name of the library to store newly calculated factors.
Field to save
Selects the field to store newly calculated factors.
Read data from
Selects the name of the library with the experimental data.
Search partners in
Selects the names of libraries with known factor values; select acceptor libraries when calculating donor factors, donor libraries when calculating acceptor factors.
Buttons: Calculate factors
Selects whether the new factors will be of the donor or the acceptor type.
Buttons: Kind of factors
Selects whether the new factors will be of the C or E type.
Adds new library to list with known factors.
Deletes the library in the list with known factors.
Calculates new factors from experimental data.
Terminates the process without taking any action.
This option in the MOLPRO: HBPlus menu is used to create a new training set. If one of the pre-formed training sets serves your needs, then you probably should avoid using this option and simply select a training from those offered under the HB factors: Library selection or Descriptors: Libraries selection options. However, if you do select the option Training set you’ll see the Training Set window (any factor database will be active to afford data for training set).
The following table explains the actions of the various functions:
Selects the name of the file with training set.
Field to extract value and assignment
Selects the field, containing factors for training set.
Overwrite existing file
When checked, the new training set will be create, if not checked, then new data will be add to the old training set.
Accepts selected options and begins the process.
It is not possible to determine directly the H-bond acceptor strength of weak acceptors situated near strong ones. An important example is the nitrogen atom of an amide group. It is known in that the nitrogen acceptor factor value will be small compared to that of the cabonyl oxygen. Without a correction for this effect, the usual estimation in HYBOT will result values too large. However, there is an indirect way to estimate the H-bond factor value of such a weak acceptor: use the difference between the acceptor strength for the entire group of atoms (in the example, the amide group) and the acceptor strength of the dominant acceptor atom (in the example, the carbonyl oxygen). This principle was used to generate a set of 32 of structural fragments to accomodate this situation.
When you select option Fragment definition in the MOLPRO: HBPlus menu you will see the Fragment Definition window. Each fragment contains two colored atoms. The red atom represents the dominant acceptor atom; its value was calculated in the standard way on the basis of the H-bond Factor database. The green atom represents the weak acceptor atom; its value was estimated as described in the previous paragraph. The value K is the ratio of the factor value for the green atom to that of the red atom. When the box "Not use" in the Library Selection window is not checked (recommended), HYBOT will correct fragments with weak acceptors by multiplying the value normally obtained by the factor K.
Selects the file with structural fragments.
Shows the record number of the currently selected fragment entry.
From the current record in the list, the t button takes you to the record above; the u button takes you to the record below.
Coefficient = Factor of green atom/Factor of red atom.
Creates a new fragment.
Deletes a selected fragment (under normal circumstances not recommended for any of the original 32 fragments).
Edits a selected fragment (under normal circumstances not recommended for any of the original 32 fragments).
Descriptors: Libraries selection
Use this option in the MOLPRO: HBPlus menu to select list of the work files to calculate factor values for many compounds in the library based on its chemical structure and an appropriate training set. . When you select this option the Library Selection window appears:
Selects one of the pre-formed training sets.
When not checked (recommended), the calculation of the factors will include factors from fragments.
Sets list of libraries to scan for exact structure matching.
When not checked (recommended), the calculation of the factors will include scan of the libraries.
Adds new library to list with libraries to scan.
Deletes the library in the list with libraries to scan.
Accepts selected options and jumps to the Start window.
Terminates the process with no action being taken and jumps to the Start window.
Use this option in the MOLPRO: HBPlus menu to calculate the descriptors on the basis factor values for many compounds in the library based on its chemical structure and an appropriate training set. . When you select this option the Calculate window appears (any library, containing the structures and the fields to store the calculated descriptors will be active).
Selects the list of descriptors to calculate.
Fields to save
Selects the fields in the library to store the calculated descriptors.
Accepts selected options and calculates the descriptors.
Descriptors provided by HYBOT:
sum of atomic polarizabilities; a measure of molecular volume
largest Ca factor value
atom with greatest H-bond acceptor strength
largest Cd factor value
atom with greatest H-bond donor strength
most positive partial atomic charge
most negative partial atomic charge
total of Ca factor values
total of Cd factor values
total of positive partial atomic charges
total of negative partial atomic charges
total of absolute partial atomic charges
sum of absolute C factor values
sign of factor values ignored
total of positive partial atomic charge/Alpha
positive partial atomic charge per unit of molecular volume
total of negative partial atomic charge/Alpha
negative partial atomic charge per unit of molecular volume
total of Ca factor values/Alpha
Ca factor value per unit of molecular volume
total of Cd factor values/Alpha
Cd factor value per unit of molecular volume
sum of absolute C factor values/Alpha
C factor values per unit of molecular volume
To view the results of descriptor calculation for any compound select option Descriptors: Display in the MOLPRO: HBPlus menu and you will see the Display window (a library, containing the calculated descriptors will be active).
Allows you to calculate the descriptors for new molecule.
Opens the Print Preview window. This display shows all the data in the Display window as it will be printed. To print this screen click on the Print button. If you don’t want to print this screen, click on Close button to return to the Display window.
Descriptors: Export to Excel
You can export the calculated descriptors in a spreadsheet Microsoft Excel™. When you select option Descriptors: Export to Excel the Export window appears (a library, containing the calculated descriptors will be active).
Fields to be exported
Selects the descriptors to export.
The current record in the list, the button move above; the ¯ button move below.
Descriptors: Export to Text file
You can export the calculated descriptors in a text file. When you select option Descriptors: Export to Text file the Save as window appears (a library, containing the calculated descriptors will be active).
Type name of the text file and click Save. The Export window appears (see Descriptors: Export to Excel).
HB factors: Library selection
Use this option in the MOLPRO: HBPlus menu to select list of the work files to calculate factor values for a single compound or for many compounds in batch mode based on its chemical structure and an appropriate training set. . When you select this option the Library Selection window appears:
HB factors: Element selection
As is known, that as proton donors act usually the groups OH, NH, SH, ( less often CH ), and as proton acceptors the atoms O, N, S ( less often F, Cl, Br, I, Pi-systems ). By default (empty list of elements) the factors are calculated for all elements. At inclusion of any element in the list will be calculated the factors only for this element.
When you select option HB factors: Element selection in the MOLPRO: HBPlus menu you will see the Elements Definition window.
List of elements to be predicted
Deletes the atom in the list with proton acceptors and proton donors.
HB factors: Predict
Use this option in the MOLPRO: HBPlus menu to calculate factor values for a single compound based on its chemical structure and an appropriate training set. When you select this option the Structure Editor window appears:
Draw the chemical structure of the compound in which you are interested; then select option OK. HYBOT jumps to the Result window and shows the structure drawn with the relevant factor information in tabular form.
At this point only one marked atom is shown. To see the others click: i) on each atom what you want ii) on any line in the table.
HB factors: Predict from file
This option allows you to estimate factors for many compounds in batch mode based on chemical structure alone from the factors database. For example, you may be interested in hydrogen bonding factors for a series of compounds found in an ISISTM database. A selection of compounds from this database can be saved in *.sdf file format. Such a file can supply the chemical structural information to HYBOT so that it can then make the calculations on the entire group of compounds. In this mode, the information output is placed in a comma delimited text file that can then be imported into a spread sheet such as Microsoft ExcelTM for viewing and/or further manipulation.
When you select the option Predict from file in the MOLPRO: HBPlus menu you jump to an Open File window. You must choose the desired *.sdf file.
You can move through the directories to locate that file; once it is found click on it to select it, and then click on Open. HYBOT proceeds to calculate the hydrogen bonding factors. When finished it will place the results in a comma delimited text file in the same directory from which the *.sdf file was taken. The name of the file is pred.dat.
Chapter 4 Learning HYBOT
In the following tutorials it is assumed that you know how to perform basic operations with your computer: starting applications from Microsoft Windows, sizing, moving and scrolling through windows, opening menus and choosing menu items. In the following scenarios, click means that you should select an item by pressing the left mouse button; R-click means that you should select an item by pressing the right mouse button.
Suppose you want to find in the hydrogen bond thermodynamics database all entries that match the following criteria: hydrogen bond acceptors with amide fragments, tetrachloromethane as the solvent, and the free energy of complexation in the interval from -14 kJ/mole to -13 kJ/mole.
To select entries:
To view entries
You can view the results by scrolling through the list; click on the marked arrows to see the list of compounds matching the selection criteria.
Let us say that you want to add a new entry to the hydrogen bonding thermodynamics database. The following data need to be entered: the hydrogen bond donor, 3,5-difluoro-4-chlorophenol; the hydrogen bond acceptor, pyridine; the solvent tetrachloromethane; the free energy of complexation, -13 kJ/mole; the enthalpy of complexation, -20 kJ/mole; the complex, 1:1, the experimental method, infrared spectroscopy; the temperature, 298 K; one hydrogen bond between OH group of H-donor and nitrogen atom of H-acceptor; author, Smith A.; the literature source, Journal of Molecular Structure, 1995, Vol. 50, pp. 100-106. You may add a new entry in an existing library or create of a new library. For example, you want to add the new entry in existing library HBTHERMO.
To add a new entry:
Calculation Factors from Experimental Data
(Please don't use this procedure without special need. The calculated factor values loaded in the factor data bases of your copy of HYBOT-PLUS-2000/CHED were prepared by our specialists with long time experience in the field.)
This method is used to calculate the hydrogen bonding factors (Ca, Cd, Ea, Ed, a ,b ) for one centre in a molecule (one centre model).
Suppose you want to calculate the proton donor free energy (Cd) factors of the hydrogen bond donors. You must have a library (for example HBTHERMO, see previous exercise) in the hydrogen bond thermodynamics database with one or more entries including the structures of H-bond donors and an H-bond acceptors, the values of the free energy and enthalpy, the solvent and the temperature (see previous exercise). You can add a new factor to an existing library in Hydrogen bonding factors database or create of a new library. For example, you may want to add the new factors to a new library, FNEW. Also you must have library with known proton acceptor free energy (Ca) factors, the library CA will do.
To create a new library FNEW:
To calculate new factors from experimental data:
Prediction of Factors for a Single Chemical Structure
This method is used to calculate factors (a , b , Cd, Ca, Ed and Ea) for many centres in a molecule (many centres model).
For example, you want to calculate the C-factors of 3-methoxyphenol by using as an initial basis a libraries CA(O), CD, CD_NEW and the training set Overall2.hbp. Also you want to scans the content of libraries CA(O), CD, CD_NEW in Hydrogen bonding factors database and, if the exact structure is not found, to calculate the factors with (recommended) including the fragments defined in Tools/MOLPRO: HBPlus/Fragment Definition (see Fragment definition window).
Scan the libraries that are the same as training set.
(RECOMMENDED TRAINING SET IS Overall2.hbp)
To predict new factors from chemical structure:
To view results of predicting of new factors:
Prediction Factors for File of Chemical Structures (batch mode)
Use this method to calculate the factors (a , b , Cd, Ca, Ed and Ea) for many multicentred` compounds from an *.sdf file of chemical structures. The output will be a comma delimited text file that can be imported into a spreadsheet such as Excel™. From this spreadsheet you can manipulate the data further and/or view the results.
Suppose you want to calculate the C-factors for a series of compounds from a file in which the structures are in the *.sdf format (you must create this file from a chemical database, for example ISIS/Base™), using as an initial basis a libraries CA(O), CD, CD_NEW and the training set Overall2.hbp. Also you want to scans the content of libraries CA(O), CD, CD_NEW in Hydrogen bonding factors database and, if the exact structure is not found, to calculate the factors with (recommended) including the fragments defined in Tools/MOLPRO: HBPlus/Fragment Definition (see Fragment definition window).
To predict new factors for a series of chemical structures:
To view results of predicting new factors:
In the same directory from which you took the *.sdf file, find a new ASCII comma delimited text file with the name pred.dat. The output format is: compound identifiers, factor values, and atom type/location, e.g. N23, a nitrogen atom acceptor found in position 23 of the molecule or HO16, a hydrogen bond donor found on the oxygen atom at 16 position of the molecule. Some times the compound identifiers are not picked up in this operation; in this case the first entry of each row will start with a comma, ’’,’’. It is advisable to import this file into a spreadsheet; some manipulation of the data may be required to make them understandable.
Prediction of Factors and Calculation Descriptors for Library of Chemical Structures
Use this method to calculate the descriptors on the basis factor values for many multicentred` compounds from an library of chemical structures.
Suppose you want to calculate all descriptors for a series of compounds from a new library DRUGS, using an import of any *.sdf file and using as an initial basis a libraries CA(O), CD, CD_NEW and the training set Overall2.hbp. Also you want to calculate the factors with (recommended) including the fragments defined in Tools/MOLPRO: HBPlus/Fragment Definition (see Fragment definition window).
To create a new library DRUGS and to import *.sdf file:
To calculate descriptors for a library of chemical structures:
To view results of calculating descriptors:
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