The lipophilic behaviour of organic compounds: 1. An updating of the hydrophobic fragmental constant approach

The lipophilic behaviour of organic compounds:1. An updating of the hydrophobic fragmental constantapproach

Raimund Mannhold1*, Roelof F. Rekker2, Karl Dross3, Greetje Bijloo2 and Gerrit de Vries4

1Department of Lasermedicine, Molecular Drug Research Group, Heinrich-Heine-UniversitaÈt, UniversitaÈtsstraûe 1, 40225 DuÈsseldorf,

Germany2LeidenyAmsterdam Center for Drug Research, Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit Amsterdam,

De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands3Department of Brain Research, Heinrich-Heine-UniversitaÈt, UniversitaÈtsstraûe 1, 40225 DuÈsseldorf, Germany4Department of Analytical Chemistry, Faculty of Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam,

The Netherlands

Abstract

In the ®rst part of this paper we brie¯y describe

experimental (octanolywater partitioning) as well as

computational approaches to quantifying molecular lipo-

philicity.

The central section focuses on the hydrophobic fragmental

constant approach (Sf -system) as developed by Rekker and

his group, starting in the early seventies. The original

approach has been extended and revised a number of times;

the most recent updating is presented here. It is followed by

a detailed description of how to apply the correction factor

CM. The practical procedure of Sf-calculations is described

for some examples and the validity of these calculations is

veri®ed by comparison with other calculation methods and

experimental data.

517 Quant. Struct.-Act. Relat., 17 (1998) # WILEY-VCH Verlag GmbH, D-69469 Weinheim 0931-8771/98/0510-0517 $17.50+.50/0

The lipophilic behaviour of organic compounds QSAR

1 Introduction

The importance of lipophilicity as a descriptive parameter

in bio-studies is nowadays acknowledged by its frequent

use in an increasing number of research ®elds including

medicinal chemistry, toxicology, pharmaceutical sciences

and environmental search. An emerging new ®eld of

application of lipophilicity is in combinatorial chemistry.

In the design of compound libraries, experimental or

computed lipophilicity data can be used as estimates for

oral drug absorption as an important contribution to

bioavailability. The widespread application of lipophilicity

to biophysical processes involving xenobiotics, in parti-

cular as a screening tool, explains the urgent need for both

valid and quick procedures to quantify molecular lipophi-

licity.

Lipophilicity is de®ned by the partitioning of a solute

between aqueous and nonaqueous phases. Its quantitative

descriptor, the partition coef®cient P or, in its logarithmic

form, log P, expresses the ratio of monomeric, neutral

solute concentrations in the organic (CO) and aqueous

phase (CW) of a two-component system under equilibrium

conditions:

P � log CO ÿ log CW �1�

The so-called shake-¯ask experiments necessary for

determining log P are tedious, time-consuming and demand

a high purity of the investigated compounds. This latter fact

is not always recognized by investigators, so that many

inconsistencies are evident in the literature. In this respect

the reader is referred to log P data of environmentally

important chemicals (Table 1) and a series of aliphatic

alcohols (Table 2).

The disadvantages and shortcomings in experimental log P

provoked an intensive search for alternative lipophilicity

descriptors. In the present paper we report on development

and current status of the ®rst fragmental procedure for

* To receive all correspondence Raimund Mannhold, Institut fuÈr

Lasermedizin, AG Molekulare Wirkstoff-Forschung, Heinrich-Heine-Uni-

versitaÈt DuÈsseldorf, UniversitaÈtsstr.1, D-40225 DuÈsseldorf, Deutschland

Key words: Octanolywater partition, hydrophobic fragmental

constant approach, log P calculation, Sf, magic constant CM

calculating log P, the hydrophobic fragmental constant

approach or S f-approach.

2 Determination of Lipophilicity

2.1 Octanolywater Partitioning

The organic solventywater system of choice to determine

log P is 1-octanol. Advantages of this solvent, and a

discussion of its physico-chemical properties, are summar-

ized by Leo et al. [1], Smith et al. [2], Dearden [3] and

Kubinyi [4]. Belying its simple de®nition, the determination

of log P quite often poses practical problems, particularly in

the case of polar or highly lipophilic solutes. Impurity and

instability of the solute can produce unreliable experimental

data. Among the various precautions to be considered for an

accurate measurement of log P are presaturation of the

phases, the use of low solute concentrations, centrifugation

for a proper separation of the phases, and the determination

of solute concentration in either phase. Detailed summaries

of the experimental prerequisites for precise measurements

of partition coef®cients, including the aspects of ion-

correction, are given e.g. by Leo et al. [1], Kubinyi [4]

and Taylor [5].

For compounds of low solubility and compounds with low

UV absorbance or rather high log P, special methods of

measurement or alternative lipophilicity parameters (for

reviews see Dearden and Bresnen [6]; Hersey et al. [7]) had

to be devised, such as the slow stirring technique [8], the

®lter probe [9] and its revised ®lter chamber technique [7],

the ¯ow-injection extraction [10] and the microscale

partitioning method [11]. Another recently developed

technique for log P measurement is centrifugal partition

chromatography [12±15].

For ionizable compounds, BrandstroÈm [16] was the ®rst to

use a potentiometric titration technique. Differences in pKa,

obtained in aqueous titrations and in the presence of

octanol, were related to log P. Seiler [17] modi®ed this

technique to determine pKa and log P from a single titration.

The technique has now been re®ned to allow treatment of

substances with multiple ionization constants, ion-pair

partitioning and self-association reactions leading to the

formation of oligomers [18±21]. Regarding determination

of log P and pKa by titration also the work of Clarke

deserves mention [22±24].

2.2 Calculation Approaches

The Hansch group developed the p-system as the ®rst

method of calculating log P [25]. Shortcomings in the p-

Table 1. Reported log P values of some environmentallyimportant chemicals

compound log Pav n H L D (H-L) log P* Sf1998

benzene 2.08 10 2.34 1.56 0.78 2.13 2.11

toluene 2.59 7 2.94 2.11 0.83 2.73 2.63

chlorobenzene 2.58 4 2.89 2.18 0.66 2.89 2.84

phenol 1.49 12 2.20 0.62 1.58 1.46 1.55

pentachlorophenol 4.90 6 5.86 3.81 2.05 5.12 5.19

hexachlorobenzene 5.27 6 6.27 4.13 2.14 5.73 6.48

naphthalene 3.36 8 3.59 3.01 0.58 3.30 3.40

biphenyl 3.91 6 4.17 3.16 1.01 4.01 4.02

log Pav� averaged log Poct-value; n� number of literature data;

H� highest and L� lowest observed log P value; D(H-L)�HyL

difference; log P*� log P value of preference according to Hansch;

Sf1998� calculated log P using fragment values from the appendix

Table 2. Mutual comparison of log P data of aliphatic alcohols

nr Compound log Pav n H L D(H-L) log P* Sf1998

1 CH322OH ÿ0.68 6 ÿ0.52 ÿ0.82 0.30 ÿ0.77 ÿ0.72

2 CH322CH222OH ÿ0.28 7 ÿ0.15 ÿ0.37 0.22 ÿ0.31 ÿ0.21

3 CH322(CH2)222OH 0.28 2 0.30 0.25 0.05 0.25 0.31

4 (CH3)222CH22OH 0.05 1 Ð Ð Ð 0.05 0.10

5 CH322(CH2)322OH 0.78 7 1.02 0.32 0.70 0.88 0.83

6 (CH3)222CH22CH222OH 0.75 3 0.83 0.65 0.18 0.65 0.83

7 CH322CH222CH(CH3) 22OH 0.71 2 0.81 0.61 0.20 0.61 0.61

8 (CH3)322C22OH 0.44 3 0.59 0.35 0.24 0.35 0.40

9 CH322(CH2)422OH 1.48 3 1.56 1.40 0.16 1.56 1.35

10 (CH3)222CH22(CH2)222OH 1.25 3 1.42 1.16 0.26 1.16 1.35

11 CH322(CH2)222CH(CH3) 22OH 1.26 2 1.34 1.19 0.15 Ð 1.13

12 (CH322CH2)222CH22OH 1.29 2 1.37 1.21 0.16 1.21 1.13

13 CH322CH222C(CH3)222OH 1.02 2 1.15 0.89 0.26 0.89 0.91

14 CH322C(CH3)222CH222OH 1.30 3 1.36 1.21 0.15 1.31 1.35

15 (CH3)2CH22CH(CH3) 22OH 1.28 1 Ð Ð Ð 1.28 1.13

log Pav� averaged log Poct-value; n� number of data included in the averaging procedure; H� highest and L� lowest

observed log P value; D (H=L difference; log P*� log P value of preference according to Hansch; Sf1998� calculated log P

using fragment values from the appendix and the necessary CM corrections for secondary and tertiary alcohols (see rule 8 in

Table 11)

QSAR Raimund Mannhold, Roelof F. Rekker, Karl Dross, Greetje Bijloo and Gerrit de Vries

518 Quant. Struct.-Act. Relat., 17 (1998)

system led Rekker to develop the fragmental contribution

concept [26, 27±29]. Since the de®nition of a fragment is

not unambiguous, Broto et al. [30] and later on others

developed calculation systems based on atomic contribu-

tions. Finally, some recent approaches re¯ect the impact of

3D-structure on molecular lipophilicity or use molecular

orbital indices to quantify log P (for an overview see

Table 3).

2.2.1 Fragmental Methods

The ®rst hydrophobic fragmental system was developed by

the Rekker group [26, 28, 29]. A data set of more than 1000

experimental log Poct values of simple organic compounds

was used to derive a list of about 160 fragmental values by

regression analysis, hence this approach has been labeled

"reductionistic". This system is based on the relation:

log P � Sf �Pni�1

ai � f i �Pmi�1

k i ? CM �2�

where f is the hydrophobic fragmental constant, a indicates

the number of a given fragment in a molecule, CM denotes a

correction factor and ki gives its frequency.

In 1975 Leo et al. [31] published a fragmental system,

based on the principles of `̀ constructionism''. This

approach started with some basic fragmental values,

obtained by experimental measurement of a small set of

the simplest possible molecules and then constructed the

fragment set by applying numerous correction factors in

order to maintain the desired adaptation of new material in

the system [31±35]:

log P � CLOGP � San � f n � Sbm � Fm �3�

where f is the fragmental constant, a is the incidence of

fragments, F is a correction factor and b is the frequency of

correction factors.

A further contribution to fragmental approaches stems from

Klopman. The Computer Automated Structure Evaluation

(CASE) program is able to identify the most important

fragments, or sometimes single atoms, required for a good

log P estimation [36].

Another new and very effective approach is the atomyfrag-

ment contribution method introduced by Meylan and

Howard [37] and available as the KOWWIN software.

Table 3. Programs and methods for the calculation of log P

Program Method References

Programs and methods based on fragmental methods

CLOGP HanschyLeo Leo et al. [31], Hansch and Leo [32], Leo [33-35]

Sf Rekker Nys and Rekker [26], Rekker [28], Rekker and de Kort [29]

PROLOGP_cdr Rekker, original version Darvas et al. [71]

Sf-SYBYL Rekker, revised version Rekker and Mannhold [63], Mannhold et al. [68, 69]

SANALOGP_ER Rekker, extended revised version Petelin et al. [72]

KLOGP(CASE) computer-identi®ed fragments Klopman et al. [36]

KOWWIN atomyfragment contributions Meylan and Howard [37]

Programs and methods based on atomic contributions

MOLCAD atomic values Broto et al. [30],

Tsar 2.2 atomic values Ghose and Crippen [38-40],

ATOMIC5 atomic values Ghose et al. [41]

CHEMICALC-2 atomic values Suzuki and Kudo [42]

SMILOGP atomic contributions Convard et al. [43]

AUTOLOGP autocorrelation Devillers et al. [73]

GLOGP atomic fragments Viswanadhan et al. [74]

Programs and methods based on molecular properties

Ð charge densities Klopman and Iroff [75]

BLOGP molecular descriptors Bodor and Huang [76],

SCILOGP molecular descriptors Bodor et al. [77]

CLIP mol. lipophilicity potential Gaillard et al. [78]

HINT mol. lipophilicity potential Kellogg et al. [50]

ASCLOGP approximate surface Ulmschneider [52], van de Waterbeemd et al. [53]

MOLFESD free energy surface densities Pixner et al. [79]

Ð structural parameters Moriguchi et al. [80, 81]

Ð solvatochromic parameters Leahy [82]

Ð graph theoretical descriptors Niemi et al. [83]

Ð molar volume and H-bonding Raevsky et al. [84]

Ð molecular descriptors Sasaki et al. [85]


Quant. Struct.-Act. Relat., 17 (1998) 519

2.2.2 Atom-based Methods

Fragmentation of a molecule is somewhat arbitrary and

there are advantages and disadvantages of any fragmenta-

tion mode. Fragments larger than a single atom can be

selected, so that signi®cant electronic interactions are

comprised within one fragment, and this is perceived as

the main advantage of using fragments. The advantage of

using an atomic fragmentation approach is that ambiguities

are avoided, the disadvantage being that a steadily

increasing number of atom types is needed to describe a

reasonable range of molecules, unless atomic charges are

calculated to distinguish between various electronic forms

of the same, or similarly hybridised atom. Atom level

fragment schemes work well in many instances, but a

common shortcoming is the failure to deal with long-range

interactions such as found in p-nitrophenol [35].

The GhoseyCrippen approach [38±41] is the most widely

used atom-based method. Atom-based procedures avoid

correction factors; correspondingly, calculations with the

GhoseyCrippen system are performed according to:

log PGC � Sni � ai �4�

where ni is the number of atoms of type i and ai is the

contribution of an atom of type i.

In 1990 Suzuki and Kudo [42] published their variant for

log P calculation. It uses both atomic and fragmental

contributions. A group-contribution model without usage

of correction terms is proposed.

Convard et al. [43] presented a program that generates an

extended connectivity matrix from the SMILES code of a

given molecule, which allows the determination of the

atomic code for an atomic fragment and then the attribution

of its contribution to lipophilicity.

A further new atom-additive method was recently published

by Wang et al. [44].

2.2.3 Methods Based on Molecular Properties

Re¯ecting the `̀ composite nature'' of lipophilicity encoding

both steric and polar properties, recent methods have been

proposed that utilize molecular properties of the entire

solute molecule (charge densities, molecular surface area,

volume and electrostatic potential) to calculate log P. These

models attempt to circumvent various shortcomings of the

fragmental approaches such as simpli®cation of steric

effects or the failure to calculate log P for structures with

unknown fragments.

Considering the excellent correlation between partition

coef®cients and solvatochromic parameters (cavity size,

dipolarity and hydrogen bonding acceptorydonor ability),

derived by the Taft group [45, 46], it seemed reasonable to

use a molecule's electrostatic potential together with an

estimate of its size as theoretical predictors for calculating

log P. Among others Du and Arteca [47] and Brinck et al.

[48] have developed this approach.

In the early nineties Kantola and coworkers presented an

atom-based parametrization, using atomic contributions to

surface area (Si), atomic numbers (N) and net charges (Dq)

associated with each atom and with the molecule in a

de®ned conformation [49]. This enabled them to compute a

conformationally dependent lipophilicity contribution, p,

which equals the macroscopic property log P if no more

than one conformer is involved in each phase.

Various other approaches have been proposed to consider

conformational freedom in log P calculations, such as the

HINT program [50] or the method based on molecular

lipophilic potentials developed by the Testa group [51].

Alternatively, conformation-dependent log P values may be

obtained by approximate surface calculations using the

program ASCLOGP introduced by Ulmschneider [52, 53].

The impact of three-dimensional aspects on log P is also

considered in the recent papers of Masuda et al. [54], Cash

[55] and Waller [56].

The next step in computing conformationally dependent

lipophilicities involves the determination of the population of

each conformation in both phases. Partition coef®cients will

then need to be computed by summation over all conforma-

tions. Some progress towards this goal has been made by

Richards et al. [57] who developed the HYDRO program.

3 Development and Current Status of the Sf -system

The study of Quantitative Structure-Activity Relationships

(QSAR) was initiated by Hansch and co-workers in the

early sixties [58±60]. Actually, it was the ®rst time that

lipophilic behaviour of a compound so clearly presented

itself as a parameter of high importance in describing

biological activity:

log BR � a log P � bs� cES � d �5�

where BR� biological response; P� partition coef®cient;

s�Hammett constant; ES�Taft parameter; and a, b, c,

d� constants generated by means of regression analysis.

The increasing need of rapidly attainable lipophilicity

parameters activated the search for calculative approaches.

The ®rst goals were reached by Fujita et al. in 1964 [25]



with their p-method. In analogy to the procedure, followed

by Hammett [61] for the concept of his Hammett constant,

they evaluated lipophilicity as follows:

log P�RX� ÿ log P�RH� � r � p�X� �6�

P(RX) and P(RH) represent partition coef®cients of RX and

RH, RX indicates a structure derived from RH by replacing a

H-atom by substituent X; p(X) is de®ned as the hydrophobic

substituent constant, i.e. the lipophilicity contribution of

substituent X when replacing H by X; r denotes a constant

dependent on the nature of the partition system.

The incorrect de®nition of hydrogen lipophilicity, equalling

zero, and the folding-correction, applied in the p-system,

led Rekker and his group to develop the ®rst fragmental

approach to calculate molecular lipophilicity, known in the

literature as the Sf-approach. With this approach the

availability of an experimental log P for a parent molecule

is no longer necessary and the de-novo calculation of

unmeasured structures was possible for the ®rst time. The

development of the Sf-system comprised three main phases.

Period 1973±1979: Accurately measured experimental

log P for about 100 simple organic structures (mainly

selected from literature sources) served as an initial data set

to derive fragmental constants by means of Free-Wilson

type regression analyses, continuously ®ne-tuned by a

stepwise enlargement of the data sets. The ®rst period

resulted in a valuable system for log P calculation based on

126 fragment values. Fragmentation is performed in such a

way that functional groups with recognizable direct

resonance interaction are left intact. Fragments range from

atoms over substituents to complicated, in particular

heterocyclic ring structures; fragments are differentiated

according to aliphatic or aromatic attachment.

The hydrocarbon fragments were treated separately; their f-

values are given in Table 4 and at that time these values

were considered to be satisfactory. The correlation between

f and the numbers of C and H atoms (nC and nH) is given by:

f � 0:137��0:016�nC � 0:204��0:028�nH

ÿ 0:013��0:057� �7�n � 10; r � 0:9982; s � 0:041; F � 1090; jDj � 0:026

Values in parentheses are 95% con®dence limits. jDjrepresents the averaged absolute residuals; this ®gure

allows a quick judgement of the overall result of the

correlation.

An important outcome of the regression analyses was the

detection of systematic differences between experimental

log P and log P-calculations based on the summation of

fragment values. Differences between measurement and

calculation could be attributed to chemical characteristics of

the molecules, which in turn allowed the de®nition of

correction rules for log P calculation. Among the prime

correction rules to be detected was the so-called proximity

effect, which describes the presence of electronegative

centers in a molecule separated by 1 or 2 carbons. Later on

the system of correction rules was extended to other

chemical features, such as aromatic condensation, cross-

conjugation or hydrogen-bonding. A closer inspection of

the correction values needed for adequately calculating

log P revealed the surprising fact that they represent

multiples of a constant value of 0.289, which came to be

known as the `̀ magic constant'' (CM), which proves to be of

great importance in restoring imbalances between experi-

mental log P and calculations done by merely adding

fragmental values. This approach as developed in the ®rst

period is known in the literature as the original Sf-system.

Period 1979±1992: Although the system operated success-

fully, the Rekker-group did not feel fully satis®ed about a

number of intriguing points:

. The bad ®t of aliphatic hydrocarbon log Poct with Sf-

values (Table 5). The greater part of them had to be

rejected as outliers in the ®nal development of the

original Sf-system, as shown e.g. by 8 outliers among 14

calculation examples in Table 5.

. The irregular ®t of log Poct for simple halo-alkanes with

calculation data. Table 6 lists seven miscalculations

among thirteen mono-halogenated alkanes.

. The correction-factor of ÿ0.46 for structures with

electronegativity facing alkyl bulk (as shown below)

and the impossibility of connecting this correction with

the magic constant.

Table 4. Hydrocarbonaceous fragments from the original f-system (see Eq. 7)

Fragment f fest D

C6H5 1.836 1.829 0.007

C6H4 1.664 1.625 0.039

C6H3 1.416 1.421 0.005

C6H2 1.165 1.217 ÿ0.052

CH3 0.691 0.736 ÿ0.045

CH2 0.528 0.532 ÿ0.004

CH 0.326 0.328 ÿ0.002

CH255CH 0.906 0.873 0.033

C 0.177 0.124 0.053

H 0.167 0.191 ÿ0.024

jDj 0.026

f� fragment values as published by Nys and Rekker [27]; fest� fragment

values obtainable from Eq. 7; D� f7 fest ; jDj � averaged absolute

residuals



To treat these problems, the further revision of the Sf-

system gave great care to a correct tracing of CM. A set of

15 structure pairs (C6H5±(CH2)1 or 2±X versus C6H5±X),

with X representing an electronegative substituent, revealed

a fairly constant difference between f Xar and f Xal of 0.87

(� 0.06), close to three times the original CM of 0.289. It

became more and more clear, however, that a CM-value of

0.87y4 rather than 0.87y3 would be preferable for renewing

the f-system and the value of CM was revised to 0.219.

Conformational aspects were also investigated in this

period. Pleiss and Grunewald [62] studied a set of

compounds with formula patterns shown in Figure 1. These

authors compared CLOGP data with original Sf data and

established calculation rules for both systems. Rekker and

Mannhold [63] applied the revised Sf-system to the

investigated structures and determined that the differences

in log P of the conformational isomers (Figure 1) could best

be expressed by a decrease of 1 CM (�0.219) for gauche

conformations in the calculated Sf of the corresponding

trans-antiplanar conformation. Comparable differences are

present in more simple cis-trans isomeric pairs with double

C bonds.

Details of the revised Sf-system are found in Rekker and

Mannhold [63].

Period 1992±1998: The application of the rules postulated

for Sf corrections as proposed in the 1992 version raised

some problems in the calculation of halogenated structures.

These troubles, already mentioned in Table 6, forced us to

undertake a serious updating. In order to get suf®cient grip

on the complex pattern of halogen presence in aliphatic

hydrocarbon structures we assembled a series of 48 log Poct

data from the available literature (Tables 7 and 8). The

correlation of the tabulated log P values with uncorrected Sf

values (i.e. without application of CM) is of rather limited

quality:

Sfunc � 1:035��0:105� log P ÿ 0:477��0:276� �8�n � 48; r � 0:9458; s � 0:414; F � 390; jDj � 0:41;

D � ÿ0:39

In this series 25 of 48 data belong to simple mono-

halogenated n-alkanes. They were incorporated in Eq. 9

applying the f-halogen values of 1992.

Sf �1992� � 0:949��0:023� log P ÿ 0:061��0:078� �9�n � 25; r � 0:9984; s � 0:070; F � 7196; jDj � 0:21;

D � ÿ0:21

Eq. 9 was improved by up-corrections of 0.219 for Cl, Br

and I, leaving F unchanged:

Table 5. log Poct data versus Sf 1979-calculations for hydrocarbo-naceous molecules

Compound log Poct Sf1979 D

(H2) 0.45 a 0.36 0.09

CH4 1.09 b 0.88 0.21

CH322CH3 1.81 b 1.40 0.41

CH255CH2 1.13 b 1.04 0.09

CH��CH 0.37 b 0.67 ÿ0.30

CH322CH222CH3 2.36 b 1.92 0.44

CH322(CH2)222CH3 2.89 b 2.44 0.55

CH322(CH2)322CH3 3.39 b 2.96 0.43

cyclo-propane 1.72 b 1.56 0.16

cyclo-pentane 3.00 b 2.60 0.40

cyclo-hexane 3.44 b 3.11 0.33

benzene 2.13 c 2.02 0.11

toluene 2.73 d 2.54 0.19

naphthalene 3.30 e 3.30 0.00

Experimental log P data from literature (a-e) are compared with Sf

calculations (version 1979, ref. [29]) for aliphatic hydrocarbons; mis-

calculations are given in bold italics

a: Vittoria et al. [86]; b: Jow and Hansch [87]; c: Fujita et al. [25]; d:

Church and Hansch [88]; e: Kim and Hansch [89]

Table 6. log Poct data versus Sf1979-calculations for mono-halogenated alkanes

Compound log Poct Sf1979 D

CH3F 0.51 a 0.23 0.28

n-C4H9F 2.00 b 1.78 0.22

n-C5H11F 2.33 c 2.30 0.03

CH3Cl 0.91 a 0.76 0.15

C2H5Cl 1.43 a 1.28 0.15

n-C3H7Cl 2.04 a 1.80 0.24

iso-C3H7Cl 1.90 a 1.80 0.10

n-C4H9Cl 2.64 a 2.32 0.32

CH3Br 1.19 a 0.95 0.24

C2H5Br 1.61 a 1.47 0.14

n-C3H7Br 2.10 c 1.99 0.11

CH3I 1.51 a 1.27 0.24

C2H5I 2.00 c 1.79 0.21

Experimental log P data from literature (a-c) are compared with Sf

calculations (version 1979, ref. [29]) for mono-halogenated alkanes;

miscalculations are given in bold italics

a: Jow and Hansch [87]; b: Gould and Hansch [90]; c: Hansch and

Anderson [91]

Figure 1. General structures of benzonorbornenes used by Pleissand Grunewald [62] for developing correction factors forconformational isomers.

This ®gure was taken from Rekker, R.F. and Mannhold, R.,Calculation of drug lipophilicity. The hydrophobic fragmentalconstant approach. VCH publishers, Weinheim (1992) with kindpermission of the copyright owner.



F Cl Br I

1992 ÿ0.213 0.057 0.258 0.570

1998 ÿ0.213 0.276 0.477 0.789

With the resulting relation:

Sf �1998� � 0:963��0:016� log P � 0:096��0:049� �10�n � 25; r � 0:9993; s � 0:048; F � 15986; jDj � 0:05;

D � ÿ0:01

the number of miscalculations, listed in Table 6, is reduced

to one. The outlying value for n-C5H11F might indicate a

faulty log P determination, as substantiated by a correspon-

dingly deviating CLOGP calculation.

The remaining 23 structures (Table 8), included in Eq. 8,

were subdivided into three groups and studied separately.

The ®rst section of Table 8 includes three iso-structures

(no. 1±3) and seven di-halogenated alkanes with two or

three C-separations between the halogens. Their behaviour

in Sf-calculations is identical to the observations from

Table 7, no extra CM corrections are needed. The

halogenation pattern in section two (2 halogens on the

same C) requires an extra CM to be added in the calculation.

The third section (3 halogens on the same C) demands for a

higher up-correction with four extra CM; the correct ®tting

of the ¯uoro-atom (no. 18) can only be achieved by the

application of 5 CM .

In contrast to the structures described so far, which exhibit

systematic correction patterns, satisfactory rules for CM

application are currently not available for per-halogenated

compounds, even when applying the above derived

correction rules:

compound log P Sf kn

CF4 1.18 0.35 4

CCl4 2.83 2.09 3

CBr4 3.42 2.89 2

Another point of current interest in ®ne-tuning Sf calcula-

tions concerns resonance interaction. The resonance inter-

action of phenyl and carboxyl group in benzoic acid causes

a rise in f (COOH) of 0.876, corresponding to 4 CM. Ortho-

substitution can force the COOH group out of its planar

orientation with respect to the phenyl group (necessary for

full resonance interaction). Complete decoupling, caused by

suf®cient bulk of the R-groups, fully transforms the COOH

character from aromatic ( f�ÿ0.066) to aliphatic

( f�ÿ0.942).

A second example is biphenyl, which requires 1 CM in its

calculation procedure due to the presence of aryl-aryl

conjugation. With an appropriate ortho-substitution this

conjugation interaction vanishes and the extra CM can be

ignored.

Table 9 presents a selection of alkyl-substituted benzoic

acids. The reported literature values of the 4- and 2-methyl

derivatives confront us with a problem. In a recent data-

compilation [64] the asterisked values: 2.27 for 4-methyl-

and 2.46 for 2-methyl-benzoic acid are those of ®rst choice.

The Pomona data collection from 1983 [65] asterisked 2.18

for 4-methyl benzoic acid, however. These discrepancies

Table 7. Lipophilicities of mono-halogenated n-alkanes

nr Compound log Poct Sf1992 D S f 1998 D

1 CH3F 0.51 a 0.51 0.00 0.51 0.00

2 n-C4H9F 2.00 b 2.07 ÿ0.07 2.07 ÿ0.07

3 CH3Cl 0.91 a 0.78 0.13 1.00 ÿ0.09

4 C2H5Cl 1.43 a 1.30 0.13 1.52 ÿ0.09

5 n-C3H7Cl 2.04 a 1.82 0.22 2.04 0.00

6 n-C4H9Cl 2.64 a 2.34 0.30 2.56 0.08

7 n-C5H11Cl 3.11 c 2.86 0.25 3.08 0.03

8 n-C6H13Cl 3.65 d 3.38 0.28 3.60 0.06

9 n-C7H15Cl 4.15 e 3.90 0.25 4.11 0.04

10 n-C8H17Cl 4.73 d 4.42 0.31 4.63 0.10

11 CH3Br 1.19 a 0.98 0.21 1.20 ÿ0.01

12 C2H5Br 1.61 a 1.50 0.11 1.72 ÿ0.11

13 n-C3H7Br 2.10 f 2.02 0.08 2.24 ÿ0.14

14 n-C4H9Br 2.75 e 2.53 0.22 2.76 ÿ0.01

15 n-C5H11Br 3.37 e 3.06 0.31 3.28 0.09

16 n-C6H13Br 3.80 e 3.58 0.22 3.80 0.00

17 n-C7H15Br 4.36 e 4.10 0.26 4.32 0.04

18 n-C8H17Br 4.89 e 4.62 0.27 4.84 0.05

19 CH3I 1.51 a 1.29 0.22 1.51 0.00

20 C2H5I 2.00 f 1.81 0.19 2.03 ÿ0.03

21 n-C3H7I 2.54 d 2.33 0.21 2.55 ÿ0.01

22 n-C4H9I 3.08 d 2.85 0.23 3.07 0.01

23 n-C5H11I 3.62 d 3.37 0.25 3.59 0.03

24 n-C6H13I 4.16 d 3.89 0.27 4.11 0.05

25 n-C7H15I 4.70 e 4.41 0.29 4.63 0.07

D 0.21 0.004

jDj 0.21 0.05

Experimental log P data from literature (a±f) are compared with Sf

calculations (versions 1992, ref. [63] and 1998, this paper) for mono-

halogenated alkanes; D� averaged residuals; jDj � averaged absolute

residuals;

a: Jow and Hansch [87]; b: Gould and Hansch [90]; c: Debnath and Hansch

[92]; d: Abraham et al. [93]; e: Tewari et al. [94]; f: Hansch and Anderson

[91]



asked for a careful evaluation. Our ®nal choice is indicated

in Table 9. The correlation of Sf with log P, corrected for 2-

methyl- and 2,6 dimethyl-benzoic acid, is:

Sf �corr� � 1:009��0:035� log P ÿ 0:039��0:102� �11�n � 10; r � 0:9991; s � 0:034; F � 4500; jDj � 0:022

The correlation reveals a small, but signi®cant decoupling

of resonance in the 2-methyl derivative and a stronger,

although not yet complete, decoupling in the 2,6-dimethyl

derivative.

Table 10 comprises a set of mono-substituted benzoic acids.

The correlation was started up with Eq. 12 omitting

corrections in the f-summations:

Sf � 0:958�0:200� log P � 0:128�0:442� �12�n � 25; r � 0:9003; s � 0:252; F � 98:0; jDj � 0:183

The application of negative corrections for steric effects and

positive corrections for resonance enhancement (com-

pounds 17, 18, 23, 24) results in:

Sf � 0:970�0:053� log P � 0:024�0:115� �13�n � 25; r � 0:9923; s � 0:066; f � 1470; jDj � 0:054

Table 8. Lipophilic effects of halogenation in aliphatic hydrocarbons

nr Compound log P Sf1992 D kn Sf1998 D

1 i-C3H7Cl 1.90 a 1.82 0.08 0 1.82 0.08

2 i-C3H7Br 2.14 b 2.02 0.12 0 2.02 0.12

3 i-C4H9Cl 2.33 c 2.33 0.00 0 2.34 ÿ0.01

4 Cl-CH2-CH2-Cl 1.48 a 1.59 ÿ0.11 0 1.59 ÿ0.11

5 Br-CH2-CH2-Br 1.98 d 1.99 ÿ0.03 0 1.99 ÿ0.03

6 l-CH2-CH2-I 2.71 d 2.61 0.10 0 2.62 0.09

7 Cl-C3H6-Cl 2.00 a 2.11 ÿ0.11 0 2.11 ÿ0.11

8 Br-C3H6-Br 2.37 c 2.51 ÿ0.14 0 2.51 ÿ0.14

9 I-C3H6-I 3.02 d 3.13 ÿ0.11 0 3.14 ÿ0.12

10 Br-C3H6-Cl 2.18 e 2.31 ÿ0.13 0 2.31 ÿ0.13

11 C-F2H2 0.20 a 0.09 0.11 1 0.31 ÿ0.11

12 C-F2H-CH3 0.75 a 0.61 0.14 1 0.83 ÿ0.08

13 C-Cl2H2 1.25 a 1.07 0.18 1 1.29 ÿ0.04

14 C-Cl2H-CH3 1.79 a 1.59 0.20 1 1.81 ÿ0.02

15 C-Cl2H-CH2-Cl 1.89 f 1.66 0.23 1 1.88 0.01

16 C-BrClH2 1.41 e 1.27 0.14 1 1.49 ÿ0.08

17 I2-CH2 2.30 g 2.10 0.20 1 2.32 ÿ0.02

18 HCF3 0.64 a ÿ0.33 0.97 5 0.77 ÿ0.13

19 HCCl3 1.97 b 1.14 0.83 4 2.02 ÿ0.05

20 CH3-CCl3 2.49 a 1.65 0.83 4 2.54 ÿ0.05

21 HCBr3 2.67 c 1.75 0.92 4 2.62 0.05

22 HCClF2 1.08 a 0.16 0.92 4 1.04 0.04

23 HCCl2F 1.55 a 0.65 0.90 4 1.53 0.02

D 0.27 ÿ0.04

jDj 0.33 0.07

Experimental log P data from literature (a±g) are compared with Sf calculations (versions 1992, ref. [63] and 1998, this paper) for halogenated alkanes;

D� averaged residuals; jDj � averaged absolute residuals; kn� application of CM, as developed in this paper;

a: Jow and Hansch [87]; b: Hansch and Anderson [91]; c: Debnath and Hansch [92]; d: Gould and Hansch [90]; e: Tewari et al. [94]; f: Huang and Hansch

[95]; g: Recanatini and Hansch [96]

Table 9. Measured lipophilicities of some alkyl-benzoic acidscompared with Sf-values

nr Substituent log P Sfunc kn Sf1998 D

1 none 1.87 a 1.837 0 1.837 0.033

2 4-methyl 2.36 b 2.356 0 2.356 0.004

2.27 a

3 3-methyl 2.37 a 2.356 0 2.356 0.014

4 2-methyl 2.18 c 2.356 ÿ1 2.137 0.043

2.46 h

5 2,6-dimethyl 2.21 d 2.875 ÿ3 2.218 ÿ0.008

6 4-ethyl 2.89 e 2.875 0 2.875 0.015

7 4-propyl 3.42 f 3.394 0 3.394 0.026

8 4-iso-propyl 3.40 e 3.394 0 3.394 0.006

9 4-butyl 3.97 g 3.914 0 3.914 0.056

10 4-tert.-butyl 3.85 e 3.914 0 3.914 ÿ0.064

jDj 0.028

Sfunc: f-summation of fragments applying appendix-values and omission of

kn-corrections for no. 4 and 5; Sf1998: Sf calculation according to this

paper; D: log P ÿ Sf1998; jDj : averaged absolute residuals;

a: Fujita et al. [25]; b: Ezumi and Kubota [97]; c: Tomida et al. [98]; d:

Sotomatsu et al. [99]; e: Terada et al. [12]; f: Da, Yong-Zhong et al. [100];

g: Hayward et al. [101]; h: Huang and Hansch [95]



In No. 25 (salicylic acid) two effects apparently operate: a

resonance enhancement not different from that in the 4-OH-

derivative and the effect of hydrogen bonding, so that the

total correction will amount to �4.

The complete tabulation of the current version of revised f-

values, comprising now 169 fragments, is given in an

appendix at the end of this paper. It includes 14 new

heterocyclic fragments as well as two- and threefold

halogenated methyls.

4 Practical Procedure of Sf -calculations

4.1 The Correction Factor CM and its Application

Successful Sf calculations require a correct application of

possible correction factors, i.e. the evaluation of the second

right-hand term in Eq. 2. To that purpose Table 11 appears

very useful; the numbering of the correction rules as used in

Table 11 appears here in brackets for the sake of convenient

comparability.

(1) Saturated aliphatic hydrocarbon chains: Saturated

hydrocarbons in general (1.1) need the application of 2 CM,

as illustrated for pentane:

Sf � 2� 0:724� 3� 0:519� 2� 0:219 � 3:44

log Pobs � 3:39

Methane represents the only exception (1.2) and needs a

correction with 1 CM :

Sf � 1� 0:724� 1� 0:2045� 0:219 � 1:15

log Pobs � 1:09

(2) Saturated aliphatic hydrocarbon rings: Saturated

aliphatic hydrocarbon rings need 2 CM for correction (2.1),

as shown here for cyclopentane:

Sf � 5� 0:519� 0:438 � 3:03 log Pobs � 3:00

Cyclopropane (2.2) represents an exception with 1 CM :

Sf � 3� 0:519� 0:219 � 1:78 log Pobs � 1:72

(3) Unsaturation: A double bond needs no correction (3.1),

while a triple bond requires one negative CM (3.2). These

rules are exempli®ed by ethene and ethine:

Sf � 2� 0:519 � 1:04 log Pobs � 1:13

Sf � 2� 0:315ÿ 0:219 � 0:41 log Pobs � 0:37

(4) Extended chain conjugation: In cases of extended

chain conjugation, as present in butadiene-1,3, 2 CM should

be added to the normal f-summation:

Sf � 2� 0:519� 2� 0:315� 0:438 � 2:11

log Pobs � 1:99

C55C22C55O also has to be regarded as an example of this

type (see e.g. pyrethrolone in section 4.2).

(5) Aromatic hydrocarbons: Aromatic hydrocarbons call

for several up-corrections. Benzene (5.1) requires 1CM:

6� 0:315� 0:219 � 2:11 log Pobs � 2:13

In this calculation benzene was broken into 66CH. In case

one prefers starting with the fragment C6H5, the correction

is already present in its f-value: 161.902� 0.204� 2.11

Condensation in aromatics (5.2) calls for 1CM per

condensation site, indicated by 2 C's in the structure (a)

and correspondingly 4 C's in structure (b):

(a) �1 CM (b) �2 CM

Table 10. The effect of monosubstitution on benzoic acidlipophilicity

nr Substituent log P Sfunc kn Sf1998 D

1 none 1.87 a 1.837 0 1.837 0.03

2 3-F 2.15 a 2.076 0 2.076 ÿ0.07

3 4-F 2.07 a 2.076 0 2.076 ÿ0.01

4 2-F 1.77 b 2.076 ÿ1 1.857 ÿ0.09

5 3-Cl 2.68 a 2.565 0 2.565 0.11

6 4-Cl 2.65 a 2.565 0 2.565 0.08

7 2-Cl 2.05 b 2.565 ÿ2 2.127 ÿ0.08

8 3-Br 2.87 a 2.766 0 2.766 ÿ0.10

9 4-Br 2.86 a 2.766 0 2.766 ÿ0.09

10 2-Br 2.20 b 2.766 ÿ3 2.109 0.09

11 3-I 3.13 a 3.078 0 3.078 0.05

12 4-I 3.02 a 3.078 0 3.078 ÿ0.06

13 2-I 2.40 c 3.078 ÿ3 2.421 ÿ0.02

14 3-CH3O 2.02 a 1.906 0 1.906 0.11

15 4-CH3O 1.96 a 1.906 0 1.906 0.05

16 2-CH3O 1.59 d 1.906 ÿ1 1.687 ÿ0.10

17 3-NO2 1.83 a 1.593 1 1.812 0.02

18 4-NO2 1.89 a 1.593 1 1.812 0.08

19 2-NO2 1.46 b 1.593 ÿ1 1.374 0.09

20 3-CF3 2.95 a 2.855 0 2.855 0.09

21 3-CN 1.48 a 1.477 0 1.477 0.00

22 4-CN 1.56 a 1.477 0 1.477 0.08

23 3-OH 1.50 a 1.279 1 1.498 0.00

24 4-OH 1.58 a 1.279 1 1.498 0.08

25 2-OH 2.26 e 1.279 4 2.155 0.10

jDj 0.067

Sfunc: f-summation of fragments applying appendix-values and omission of

kn-corrections; Sf1998: Sf calculation according to this paper; D: log PÿSf1998; jDj � averaged absolute residuals;

a: Fujita et al. [25]; b: Tomida et al. [98]; c: Soderberg and Hansch [102];

d: Herzog and Swarbrick [103]; e: Hansch and Anderson [91]



Aryl-aryl conjugation (5.3), as exempli®ed by biphenyl

(c), requires 1 CM. Note: in phenanthrene (d) the

condensation effect prevails over the aryl-aryl conjugation.

(c) �1 CM

(d) �2 CM

Cross-conjugation (5.4) as it presents itself in benzophe-

none (e) calls for one CM.

(e) �1 CM

(6) Proximity effects: Proximity effects, although rather

simple in the conceptual approach, appear not so easy to

handle in an unambiguous way. Socalled 1C separations

X22CH222X (6.1), with X representing an electronegative

group, obtain an upwards correction of 3 CM. With 2C

separations X22CH222CH222X (6.2) the correction amounts

to 2 CM. Proximity effects for halogens must be treated

separately and were considered in section 3.1.

(7) H attached to electronegative groups: In structures

like HCOOH, HCONH2, HCO22NR2 the normally used f H

value of 0.204 should be replaced by 0.2045� 0.219

� 0.424, i.e., the direct connection of these H atoms

apparently gains in lipophilicity by the electronegative

character of the rest of the molecule. Other examples are

groups like 22CO ? H (aldehydes) and 22CONH2 (carbona-

mides); their f-values can be connected via 0.424 with the

groups 22CO22, 22CONH22 and 22CON22, respectively.

The relevant f-values for the cited fragments are included in

the fragment tabulation (see appendix).

(8) Electronegativity facing alkyl bulk necessitates a

negative correction of 2kn or 1kn, depending on whether

the bulk arises from a quaternary (8.1) or a tertiary C

centre (8.2). A few instructive examples are given in Table

2: for iso-propanol, sec-butanol, sec-pentanol, butanol-3

and 3-me-butanol-2 bulk resides in a tertiary C, whereas in

tert-butanol and tert-amylalcohol a quaternary C is present

next to OH.

This rule does not hold for functional groups like 22COOH

and 22COO22; the oxygen is far enough away from the

alkyl bulk to avoid this effect.

(9) Oxygen connected to aromatics: Oxygen connected

to aromatics via 1 C atom is an example of an orbital

overlap between the O atom and the p electronic system

Table 11. Correction factors for application in Rekker's revised f-system

nr Correction factor Multiples of CM Example

1 Saturated aliphatic hydrocarbon chains

1.1 general �2 n-pentane

1.2 exception: methane �1 methane

2 Saturated aliphatic hydrocarbon rings

2.1 general �2 cyclopentane

2.2 exception: cyclopropane �1 cyclopropane

3 Unsaturation

3.1 double bonds Ð

3.2 triple bonds ÿ1 ethine

4 Extended chain conjugation �2 pyrethrolone

5 Aromatic hydrocarbons

5.1 benzene �1

5.2 condensation in aromatics �1 phenanthrene

5.3 aryl-aryl conjugation �1 ¯urbiprofen

5.4 cross-conjugation �1 amiodarone

6 Proximity effects

6.1 1C-separation �3 lidocaine

6.2 2C-separation �2 morpholine

7 H attached to electronegative groups �1 formic acid

8 Elektronegativity facing alkyl bulk

8.1 bulk involving quaternary carbon ÿ2 spiperone

8.2 bulk involving tertiary carbon ÿ1 propranolol

9 Oxygen bound to aromatics via 1 carbon �1 quinidine

10 Hydrogen bonding �3 salicylic acid

11 Conformational aspects see page 522 maleic acid

12 Decoupling of resonance interaction ÿ1 to ÿ5 lidocaine

13 Resonance interaction �2 nitro-aniline



of the phenyl ring, as illustrated here for benzylalcohol

C6H522CH222OH:

Sf � 1:903� 0:519ÿ 1:448� 0:219 � 1:19

log Pobs � 1:10

(10) Hydrogen bonding as present in salicylic acid creates

an extra bond between H of the phenolic OH group and

carbonyl-O of the COOH group. This bonding phenomenon

increases lipophilicity with 3 CM.

(11) Conformational aspects: see p. 522, and exempli®ca-

tion in Figure 1.

(12) Decoupling of resonance: Neutral moieties (e.g. alkyl

groups) in ortho-position to another sustituent that is able to

undergo resonance interaction (both attached to an aromatic

ring) may perform a decoupling of resonance with regard to

the aromatic system. This will convert the lipophilicity

contribution of the aromatic substituent to a more aliphatic

value. The difference between aliphatic and aromatic

fragment values is connected with multiples of CM

depending on the resonance power of the substituent:

substituent multiples of CM

OCH3 ÿ5

COOH, CONH2 ÿ4

C55O, CONH, NHCO ÿ3

NH2 ÿ2

(13) Resonance interaction: The combination of two

groups like nitro, carboxyl or carbonamide on a phenyl

ring in para or meta position gives rise to a resonance

interaction which is responsible for increased log P values

(1 to 3 CM). Subrules could not be developed so far; for the

practical approach we propose to use an averaged correction

of 2 CM.

4.2 Example Calculations

We recommend the following procedure. We start with the

gross formula and denote the functional groups (including

hetero-fragments) fg1, fg2, . . . fgn together with their f-

values (see appendix). The atomic composition is subtracted

from the gross formula leaving CxHy as the residue. The

lipophilicity contribution of CxHy is obtained from

x f �C� � y f �H�. An evaluation of correction factors

(n ? CM) completes the calculation, as follows:

nomenclature gross formula

functional groups

structural (fg1, . . . fgn) ) individual

formula residue CxHy ) data

Correct. factors CM )Sf )

This simpli®ed approach circumvents errors, especially

when treating larger molecules with frequently occurring,

not so easily recognizable bond-situations.

The proper application of correction rules is the special

focus of the following example calculations for `̀ simple''

organic structures and more complex drug molecules.

Numbers in parentheses refer to the list of correction rules

in Table 11. We recommend that the calculations be carried

out in three decimals, with the ®nal result rounded to two

decimals.

4-nitro-aniline C6 H6 N2 O2

1 NO2 (ar.) ÿ0.039

1 NH2 (ar.) ÿ0.902

�ÿ0.941

C6H4 �1.479

��0.538

3 CM �0.657

log Pobs� 1.39 S f� 1.19

Corrections: 1 constant applies to the phenyl ring (5.1) and

2 correspond to the resonance interaction between the nitro

and the amino group (13).

phenanthrene C14H10

C14H10 �3.588

5 CM �1.095

log Pobs� 4.45 S f� 4.68

Corrections: 3 constants for the benzene rings (5.1) and 2

from ring condensations (5.2).

dioxane C4H8O2

2 O (al.) ÿ3.090

C4H8 �2.077

�ÿ1.013

4 CM �0.876

log Pobs�ÿ0.27 S f�ÿ0.14



Corrections: 2 proximity effects (6.2) over 2 carbon atoms

sum up to 4 CM

salbutamol C13H21NO3

2 OH (al.) ÿ2.896

1 OH (ar.) ÿ0.353

1 NH (al.) ÿ1.814

�ÿ5.063

C13H17 �4.909

�ÿ0.154

4±2 CM �0.438

log Pobs�Ð S f� 0.28

Corrections: The oxygen coupled to benzene via 1 C (9)

and the benzene ring (5.1) deserve 1 CM, the proximity

effect (6.2) contributes 2 CM. Electronegativity facing bulk

involving a tertiary C (8.1) entails a down-correction by 2

constants, resulting in a total of 2 CM.

lidocaine C14H22N2O

1 NHCO (ar.) ÿ1.559

1 N (al.) ÿ2.074

�ÿ3.633

C13H21 �5.727

��2.094

4±3 CM �0.219

log Pobs� 2.26 S f� 2.31

Corrections: 3 constants account for 1 proximity effect

over 1 carbon (6.1); the benzene moiety adds 1 constant

(5.1). The decoupling of resonance due to ortho dimethyl

substitution (12) causes a down-correction by 3 constants,

giving in all 1 correction factor.

amiodarone C25H29I2NO3

1 benzofuryl(-1H) �2.170

2 l (ar.) �2.892

1 CO (ar.) ÿ0.976

1 N (al.) ÿ2.074

1 O (ar.) ÿ0.450

��1.562

C16H25 �6.876

��8.438

4 CM �0.876

log Pobs�Ð Sf� 9.31

Corrections: the 4 constants correspond to 1 CM for a

benzene moiety (5.1), 1 CM for aromatic cross-conjugation

(5.4) and 2 CM for proximity over 2 carbon atoms (6.2).

Correction for the second benzene moiety is subsumed in

the benzofuryl fragment.

propranolol C16H21NO2

1 naphthalenyl 3.191

1 O (ar.) ÿ0.450

1 OH (al.) ÿ1.448

1 NH (al.) ÿ1.814

�ÿ0.521

C6H12 �3.115

� 2.594

4±2 CM �0.438

log Pobs� 2.98 Sf� 3.03

Corrections: 2 proximity effects over 2 C (6.2) add up to 4

constants; isopropyl substitution of the aliphatic N repre-

sents electronegativity facing bulk involving tertiary carbon

(8.2), as does the secondary OH function, yielding a total

down correction of 2CM.

Note: correction for aromatic rings is already subsumed in

the naphthalenyl fragment.

¯urbiprofen C15H13FO2

1 COOH (al.) ÿ0.942

1 F (ar.) 0.444

�ÿ0.498

C14H12 �3.997

� 3.499

3 CM �0.657

log Pobs� 4.16 Sf� 4.16

Corrections: correction for two aromatic rings (5.1) gives 2

and aryl-aryl conjugation (5.3) gives 1 constant.

pyrethrolone C12H16O2

1 CO (al.) ÿ1.633

1 OH (al.) ÿ1.448

�ÿ3.081

C11H15 �4.280

� 1.199

6±2 CM �0.876


Corrections: 1 proximity effect over 2 C (6.2) and 2

extended chain conjugations (4) sums to 6 constants;

electronegativity facing bulk involving a quaternary C

(8.1) down-corrects to a total of 4 CM.



sulpiride C15H23N3O4S

1 O (ar.) ÿ0.450

1 CONH (ar.) ÿ1.559

1 N (al.) ÿ2.074

1 SO2NH2 (ar.) ÿ1.440

�ÿ5.523

C14H20 �5.633

� 0.110

6±1 CM �1.095

log Pobs� 0.42 Sf� 1.20

Corrections: one proximity effect over two C (6.2), one

aromatic ring correction (5.1) and internal hydrogen

bonding between O from the methoxy group and H from

the CONH-moiety (3 constants) give a total of 6. A down-

correction by 1 CM is due to electronegativity facing alkyl

bulk (8.2).

quinidine C20H24N2O2

1 quinolinyl (-1H) 1.617

1 O (ar.) ÿ0.450

1 OH (al.) ÿ1.448

1 N (al.) ÿ2.074

�ÿ2.355

C11H18 �4.893

� 2.538

3±1 CM �0.438

log Pobs� 2.88 Sf� 2.98

Corrections: 1 proximity effect over 2 C (6.2) and the

oxygen coupled to the aromatic moiety via 1 carbon (9) give

3 constants; the electronegative hydroxy group facing a

tertiary carbon (8.2) contributes a negative constant,

resulting in a correction by 2 CM.

spiperone C23 H24 I N3 O2

1 CONH (al.) ÿ2.435

2 N (al.) ÿ4.148

1 CO (ar.) ÿ0.976

1 l (ar.) �1.446

ÿ6.113

C21H23 �7.018

� 0.905

8±2 CM �1.314


Corrections: correction for 2 aromatic rings gives 2

constants (5.1) and 2 proximity effects over 1C (6.1)

contribute 6 constants, down-correction by 2 constants for

electronegativity facing bulk involving a quaternary C

yields a total of 6 CM.

The log P values of the above 12 structures were calculated

with the application of the relevant f-values (see appendix)

and use of the CM corrections as given in Table 11.

How can one treat a structure for which reliable f-values are

not available?

Clonidine and ranitidine can be taken as examples.

Clonidine has a fragment (ar) NH22C(55NH)22NH not

included in our f-listing. A search of the literature shows

that phenylguanidine has a log P*-value of 0.53 [66].

Subtracting f (C6H5) from this value gives the fragment-

value (ar) NH22C(55NH)22NH2�ÿ1.373; further subtract-

ing 2 H(neg.) gives ÿ2.221, where upon the clonidine

calculation runs as follows:

clonidine C9H9CI2N3

2 Cl (ar.) 1.866

1 NH22C(55N)22NH (ar.) ÿ2.221

�ÿ0.335

C8H7 �2.313

� 1.958

ÿ2 CM ÿ0.438

log Pobs� 1.57 Sf� 1.52

Corrections: partial decoupling of resonance between

phenyl and NH calls for a down-correction of 2 CM; the

choice of partial decoupling was based on the analogy

between (al)NHCONH2 and (ar)NHCONH2; see appendix.

For the Sf-calculation of ranitidine we would need the

fragment (al)NH22C(NH(al))55CH22NO2. No model-struc-

tures based on this feature are available and a calculation

with this approach is currently not possible.

We give this example to demonstrate the main pitfall of

fragmental procedures: i.e. the dependence of a successful

calculation on the availability of the adequate fragments.



4.3 Comparative Validity of Sf-Calculations

The routine application of calculation procedures requires

the continual comparison of their results with experimental

data [67±70]. Useful sets of experimental octanolywater

partitioning data are the HanschyLeo listing of log P*

values [64] or the listing provided by Meylan and Howard

as part of the KOWWIN software.

We have evaluated 14 commercially available calculation

programs±representing fragmental and atom-based ap-

proaches, as well as methods based on molecular proper-

ties±for a comparative test of their predictive power [69].

The entire database consisted of 138 compounds including

simple organic structures as well as more complicated drug

molecules. Not surprisingly, the validity of the calculation

programs was far better for simple organic structures than

for drug molecules. There is a clearcut ranking in the

predictive power of the calculation procedures in terms of

the methodological approach: fragmental methods yield the

best results, followed by atom-based approaches and

procedures based on molecular properties. However, since

we did not make a comprehensive study of the methods

based on molecular properties, their comparative validity

remains to be clari®ed in future investigations.

Our current interest in the lipophilicity of halogenated

alkanes led us to compare the quality of calculation

procedures for log P of the structures summarized in Tables

7 and 8; the results are given in Table 12. Inspection of the

averaged absolute residuals indicates that Sf and AC-

D_log P are superior to KOWWIN and KLOGP for these

structures.

5 References

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Table 12. Comparative lipophilicity calculations for halogenatedalkanes

nr Compound log P Sf1998 KOWWIN ACD KLOGP

1 CH3F 0.51 a 0.51 0.77 0.51 0.61

2 n-C4H9F 2.00 b 2.07 2.25 2.10 1.83

3 CH3Cl 0.91 a 1.00 1.09 0.97 0.81

4 C2H5Cl 1.43 a 1.52 1.58 1.50 1.21

5 n-C3H7Cl 2.04 a 2.04 2.07 2.03 1.62

6 n-C4H9Cl 2.64 a 2.56 2.56 2.56 2.03

7 n-C5H11Cl 3.11 b 3.08 3.05 3.09 2.44

8 n-C6H13Cl 3.66 b 3.60 3.54 3.63 3.67

9 n-C7H15Cl 4.15 c 4.11 4.03 4.16 4.08

10 n-C8H17Cl 4.73 b 4.63 4.52 4.69 4.49

11 CH3Br 1.19 a 1.20 1.18 1.15 1.10

12 C2H5Br 1.61 a 1.72 1.67 1.68 1.50

13 n-C3H7Br 2.10 d 2.24 2.16 2.21 1.91

14 n-C4H9Br 2.75 c 2.76 2.65 2.74 2.32

15 n-C5H11Br 3.37 c 3.28 3.14 3.27 2.73

16 n-C6H13Br 3.80 c 3.80 3.63 3.80 3.96

17 n-C7H15Br 4.36 c 4.32 4.12 4.34 4.37

17 n-C8H17Br 4.89 c 4.84 4.61 4.87 4.78

19 CH3I 1.51 a 1.51 1.59 1.50 1.31

20 C2H5I 2.00 d 2.03 2.08 2.03 1.72

21 n-C3H7I 2.54 b 2.55 2.57 2.56 2.13

22 n-C4H9I 3.08 b 3.07 3.06 3.09 2.54

23 n-C5H11I 3.62 b 3.59 3.56 3.62 2.94

24 n-C6H13I 4.16 b 4.11 4.05 4.15 4.18

25 n-C7H15I 4.70 c 4.66 4.54 4.68 4.59

26 i-C3H7Cl 1.90 a 1.82 2.00 1.85 1.52

27 i-C3H7Br 2.14 e 2.02 2.08 2.03 1.81

28 i-C4H9Cl 2.33 e 2.34 2.49 2.38 1.93

29 Cl22CH222CH222Cl 1.48 a 1.59 1.83 1.41 1.66

30 Br22CH222CH222Br 1.96 f 1.99 2.01 1.82 2.24

31 l22CH222CH222I 2.71 f 2.62 2.84 2.56 2.67

32 Cl22C3H622Cl 2.00 a 2.11 2.32 1.97 2.07

33 Br22C3H622Br 2.37 e 2.51 2.50 2.33 2.65

34 I22C3H622I 3.02 f 3.14 3.33 3.02 3.08

35 Br22C3H622Cl 2.18 c 2.31 2.41 2.18 2.36

36 C22F2H2 0.20 a 0.31 0.71 0.30 0.86

37 C22F2H22CH3 0.75 a 0.83 1.13 0.65 1.17

38 C22Cl2H2 1.25 a 1.29 1.34 1.19 1.25

39 C22Cl2H22CH3 1.79 a 1.81 1.76 1.53 1.56

40 C22Cl2H22CH222Cl 1.89 g 1.88 2.01 1.68 2.01

41 C22BrClH2 1.41 c 1.49 1.43 1.41 1.54

42 I222CH2 2.30 h 2.32 2.35 2.30 2.26

43 HCF3 0.64 a 0.77 0.58 0.48 1.01

44 HCCl3 1.97 d 2.02 1.52 1.76 1.60

45 CH322CCl3 2.49 a 2.54 2.68 2.10 2.04

46 HCBr3 2.67 e 2.62 1.79 2.42 2.46

47 HCClF2 1.08 a 1.04 0.89 0.98 1.20

48 HCCl2F 1.55 a 1.53 1.21 1.40 1.40

jDj 0.06 0.17 0.07 0.25

D 0.01 0.01 ÿ0.05 ÿ0.12

Experimental log P values from origins, as indicated below, are compared

with calculated data, obtained with the fragmental methods of Rekker

(Sf1998), Meylan and Howard (KOWWIN), Sangster (ACD) and Klopman

(KLOGP). D� averaged residuals; jDj � averaged absolute residuals;

a: Jow and Hansch [87]; b: Abraham [93]; c: Tewari [94]; d: Hansch and

Anderson [91]; e: Debnath and Hansch [92]; f: Gould and Hansch [90]; g:

Huang and Hansch [95]; h: Recanatini and Hansch [96]



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Received on April 4, 1998; accepted on October 6, 1998

Appendix

In this appendix the most recent version of hydrophobic

fragmental constants in the octanol-water system (focta-

nolywater) and fragmental constants in the aliphatic

hydrocarbon-water system (fahcywater) are listed.

The abbreviation ar denotes an aromatic fragment; the left-

hand atom of the respective fragment indicates the site of its

attachment on the aromatic structure.

Fragment values, labeled with **, are calculated according

to Rekker and Mannhold: Calculation of drug lipophilicity.

The hydrophobic fragmental constant approach. VCH,

Weinheim(1992), pp 53-61.

The tabulated foct-values for CH-fragments (both aliphatic

and aromatic) were obtained from the four-decimal f Coct

and f Hoct values (see nrs 62 and 93 in the appendix).

The tabulated fahc-values were calculated by means of

fahc� 1.18 foct7 0.259 kn.

Numbers in parentheses behind (fahcywater) are the

corresponding kn's applied for mutual transfer of the

octanol-water into the aliphatic hydrocarbon-water system.

Regarding their derivation we refer to the second paper of

this series.

O ? and S ? indicate double-bonded O and S, respectively.

Structures of the heterocycles, additionally labeled by

roman numerals, are shown in a ®gure at the end of the

appendix. Fragmental values of the picturized structures



minus 1 H, removed from one of the carbon atoms, are

given; the values were derived from the composing parts of

the compounds applying optimal usage of the constant CM.

nr Fragment foctanolywater fahcywater

With carbon, with hydrogen

1 C6H5 1.903 1.987 (1)

2 C6H4 phenyl- 1.698 1.745 (1)

3 C6H3 type 1.494 1.504 (1)

4 C6H2 fragments 1.289 1.263 (1)

5 C6H 1.085 1.021 (1)

6 CH3 0.724 0.854 (0)

7 CH2 0.519 0.613 (0)

8 CH 0.315 0.371 (0)

9 CH255CH 0.834 0.984 (0)

10 CH��C 0.425 0.501 (0)

11 naphthalenyl 3.191 3.248 (2)

12 OCH3 ÿ0.821 ÿ0.969 (0)

13 ar OCH3 0.274 0.323 (0)

14 COOH ÿ0.942 ÿ3.961 (11)

15 ar COOH ÿ0.066 ÿ2.668 (10)

16 CO ? H ÿ0.991 ÿ1.946 (3)

17 ar CO ? H ÿ0.334 ÿ0.912 (2)

18 O22CH222COOH ÿ1.044

19 ar O22CH222COOH ÿ0.606

20 ar CH55CH22COO ÿ0.132 ÿ0.156 (0)

21 ar CH55CH22CO ? H ÿ0.141 ÿ0.684 (2)

22 ar CH55CH22CO ? ÿ0.565 ÿ1.185 (2)

23 benzoquinonyl (a) ÿ0.020 ÿ0.542 (2)

24 naphthoquinonyl (b) 1.486 0.976 (2)

25 anthraquinonyl (c) 3.211 2.753 (4)

26 ar C55NH ÿ1.500

27 NH22C (NH2)55N22C��N ÿ1.573

28 ar NH22C (NH2)55N22C��N ÿ0.916 **

29 CONH2 ÿ2.011 ÿ5.481 (12)

30 ar CONH2 ÿ1.135 ÿ4.188 (11)

31 CONH ÿ2.435 ÿ5.981 (12)

32 ar CONH ÿ1.559 ÿ4.689 (11)

33 ar NHCO ? ÿ1.559 ÿ4.689 (11)

34 OOCNH2 ÿ1.405 ÿ3.730 (8)

35 ar OOCNH2 ÿ0.967 ÿ2.954 (7)

36 OOCNH ÿ1.829 ÿ4.230 (8)

37 ar OOCNH ÿ1.391 ÿ3.454 (7)

38 ar NHCOO ÿ0.734

39 CONHNH ÿ3.348

40 ar CONHNH ÿ2.253

41 NHCONH2 ÿ1.860

42 ar NHCONH2 ÿ0.984

43 NHCONH ÿ2.284

44 ar NHCONH ÿ1.408 ÿ5.287 (14)

45 NCONH2 ÿ2.708

46 NCONH ÿ3.132

47 ar CH55CH22NO2 0.153 ÿ0.337 (2)

48 ar CH55CH22CONH ÿ1.367 ÿ3.944 (2)

49 CONHCONH2 ÿ1.602

50 NHNHCONH2 ÿ2.850

51 CH55N22NOH ÿ0.798 **

52 ar CH55N22NOH ÿ0.141 **

53 SCH3 0.166

54 ar SCH3 0.823

55 NHCSNH2 ÿ1.409

56 ar NHCSNH2 ÿ1.190

57 NHCSNH ÿ1.833

58 ar NHCSNH ÿ1.614

59 NCSNH2 ÿ2.257

60 NCSNH ÿ2.681

61 ar NHSO2CF3 1.254

With carbon, no hydrogen

62 C 0.1102 0.1300 (0)

63 C6 (phenyl-skeleton) 0.880 0.780 (1)

64 CBr3 2.417

65 CCl3 1.814

66 CF3 0.566

67 ar CF3 1.223

68 CI2 1.907

69 CBr2 1.283

70 CCl2 0.881

71 CF2 ÿ0.097

72 CBrCl 1.082

73 CBrF 0.812

74 CClF 0.611

75 CCl F2 0.836

76 CCl2F 1.325

77 C��N ÿ1.031 ÿ1.994 (3)

78 ar C��N ÿ0.155 ÿ0.960 (3)

79 ar C55N ÿ1.930

80 COO ÿ1.200 ÿ1.934 (2)

81 ar COO ÿ0.543 ÿ0.641 (0)

82 ar OOC ÿ0.981 ÿ1.676 (2)

83 COO22 ÿ4.967

84 ar COO22 ÿ4.091

85 CO ? ÿ1.633 ÿ2.704 (3)

86 ar CO ? ÿ0.976 ÿ1.670 (2)

87 CON ÿ2.859 ÿ6.482 (12)

88 ar CON ÿ1.983 ÿ5.189 (11)

89 ar NCO ? ÿ1.544 ÿ4.930 (11)

90 NCS ? 0.471

91 ar NCS ? 1.347

92 SCN ÿ0.405

No carbon, with hydrogen

93 H 0.2045 0.2413 (0)

94 H (neg) 0.424 0.500 (0)

95 OH ÿ1.448 ÿ3.522 (7)

96 ar OH ÿ0.353 ÿ2.748 (9)

97 NH2 ÿ1.340 ÿ3.135 (6)

98 ar NH2 ÿ0.902 ÿ2.100 (4)

99 NH ÿ1.814 ÿ2.918 (3)

100 ar NH ÿ0.938 ÿ1.625 (2)

101 SH ÿ0.046 ÿ0.054 (0)

102 ar SH 0.611

103 ar SO2NH2 ÿ1.440

104 ar SO2NH ÿ1.864

105 ar NHSO2 ÿ1.645

No carbon, no hydrogen

106 Br 0.477

107 ar Br 1.134 1.079 (1)

108 Cl 0.276

109 ar Cl 0.933 0.842 (1)

110 F ÿ0.213



111 ar F 0.444 0.265 (1)

112 I 0.789

113 ar I 1.446 1.447 (1)

114 N ÿ2.074 ÿ2.965 (2)

115 ar N ÿ0.979 ÿ1.414 (1)

116 NO2 ÿ0.915 ÿ1.598 (2)

117 ar NO2 ÿ0.039 ÿ0.564 (2)

118 NNO ÿ2.063 ÿ3.211 (3)

119 O ÿ1.545 ÿ2.082 (1)

120 ar O ÿ0.450 ÿ0.531 (0)

121 S ÿ0.558

122 ar S 0.099

123 S22S 0.320

124 SO ? ÿ2.79

125 ar SO ? ÿ2.13

126 SO2 ÿ2.83

127 ar SO2 ÿ2.07

128 ar SO2N ÿ2.288

Heterocycles

129 imidazolyl I ÿ0.046

130 pyrrolyl II 0.615

131 pyridinyl III 0.534 ÿ0.665 (5)

132 1,2,4-triazolyl IV ÿ0.937 **

133 1,2,3-triazolyl V ÿ0.499 **

134 tetrazolyl VI ÿ0.917 **

135 benzimidazolyl VII 1.241

136 uracilyl ÿ1.297

137 barbituryl ÿ1.500

138 indolyl VIII 1.902

139 carbazolyl IX 3.570 **

140 quinolinyl X 1.821 ** 0.857 (5)

141 isoquinolinyl XI 1.821 ** 0.857 (5)

142 acridinyl XII 3.110 **

143 benzotriazolyl XIII 1.227 **

144 pyrimidinyl XIV ÿ0.683 **

145 pyrazinyl XV ÿ0.464 **

146 pyridazinyl XVI ÿ0.902 **

147 quinazolinyl XVII 0.824 **

148 quinoxalinyl XVIII 1.043 **

149 phthalazinyl XIX 0.386 **

150 cinnolinyl XX 0.605 **

151 pyrido (2,3) pyrazinyl XXI ÿ0.251 **

152 phenazinyl XXII 2.550 **

153 furyl XXIII 1.086

154 benzofuryl XXIV 2.374

155 dibenzofuryl XXV 3.839 **

156 thienyl XXVI 1.613

157 benzothienyl XXVII 2.901

158 dibenzothienyl XXVIII 4.388 **

159 oxazolyl XXIX ÿ0.250 **

160 benzoxazolyl XXX 1.257 **

161 isoxazolyl XXXI ÿ0.250 **

162 benzisoxazolyl XXXII 1.257 **

163 thiazolyl XXXIII 0.300 **

164 benzthiazolyl XXXIV 1.807 **

165 benzoxdiazolyl XXXV 1.557 **

166 phenothiazinyl 3.665

167 phenylaminophenyl 3.319

168 phenyloxyphenyl 4.026

169 phenylthiophenyl 4.190

CM 0.219 0.259

Structures of the heterocycles 129±135 and 138±165, listed in the appendix

I. imidazolyl II. pyrrolyl III. pyridinyl IV. 1,2,4-triazolyl

V. 1,2,3-triazolyl VI. tetrazolyl VII. benzimidazolyl VIII. indolyl

IX. carbazolyl X. quinolinyl XI. isoquinolinyl XII. acridinyl

XIII. benzotriazolyl XIV. pyrimidinyl XV. pyrazinyl XVI. pyridazinyl

XVII. quinazinolyl XVIII. quinoxalinyl XIX. phthalazinyl XX. cinnolinyl

XXI. pyrido(2,3)pyrazinyl XXII. phenazinyl XXIII. furyl XXIV. benzofuryl



XXV. dibenzofuryl XXVI. thienyl XXVII. benzothienyl XXVIII. dibenzothienyl

XXIX. oxazolyl XXX. benzoxazolyl XXXI. isoxazolyl XXXII. benzisoxazolyl

XXXIII. thiazolyl XXXIV. benzthiazolyl XXXV. benzoxdiazolyl



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The lipophilic behaviour of organic compounds: 1. An updating of the hydrophobic fragmental constant approach