Classical and Three-Dimensional QSAR in Agrochemistry - American

partition coefficient (log PCL), and the capacity factors (log k') in the ... treatment. The MeOH-phosphate buffer (pH 7.4) eluents were prepared by v...
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Hydrophobicity Parameter of Heteroaromatic Compounds Derived from Various Partitioning Systems 1

2,3

Chisako Yamagami and Toshio Fujita 1

Kobe Pharmaceutical University, Higashinada-ku, Kobe 658, Japan Department of Agricultural Chemistry, Kyoto University, Kyoto 606-01, Japan 2

The 1-octanol-water partition coefficient (log P), the chloroform-water partition coefficient (log P ), and the capacity factors (log k') in the reversed-phase liquid chromatography (RPLC) system of (un)substituted heteroaromatic compounds were measured. The relationships of log P and log k' values with the log Ρ value were analyzed in terms of hydrogen­ -bonding property of substituents. To find out the optimal conditions to estimate the log Ρ value accurately from the R P L C system, the log k' values obtained with the ODS column using methanol-buffer (pH 7.4) mixtures as the mobile phase were examined as a function of the mobile phase composition. The use of eluents containing about 50% methanol gave the most straightforward correlation between log k' and log Ρ except for compounds having amphiprotic substituents. In mobile phases in which the water content is higher, the relationship was complicated because of an increased difference in relative hydrogen-bonding effects of partitioning phases between the two systems. A new type of parameter S for hydrogen-accepting substituents was proposed to correct their hydrogen-acceptability from solvents. CL

CL

HA

It is well known that the hydrophobicity is a very important factor affecting the biological activity. As a standard parameter of the hydrophobicity, the logarithm of the partition coefficient in the 1-octanol - water system, log P, is widely used (7), and a comprehensive compilation of log Ρ values of various organic compounds is now available (2). However, not many studies have been performed concerning log Ρ values of heterocyclic molecules (3-5) in spite of the fact that a number of biologically active compounds contain various types of heterocyclic rings. We have been accumulating log Ρ values of (un)substituted heteroaromatic compounds and analyzing them in terms of substituent effects (3,4). Their partition behavior has been found considerably different from that of the benzenoid compounds mainly because the electronic interactions between the ring heteroatom(s) and the substituents cause variations in their hydrogen-bonding ability, and these are not always easily parameterized. 3

Corresponding author. Current address: EMIL Project, Fujitsu Kansai Systems Laboratory, 2-2-6 Shiromi, Chuo-ku, Osaka 540, Japan 0097-6156/95/0606-0036$12.00/0 © 1995 American Chemical Society

Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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3. YAMAGAMI & FUJITA

Hydrophobicity of Heteroaromatic Compounds37

Recently, log Ρ values have also been estimated from capacity factors, log k\ measured with the reversed-phase liquid chromatography (RPLC) (6-8). Although this RPLC method is convenient and frequently used, standard conditions to estimate the log Ρ value do not seem to be established. The accurate estimation of log Ρ values of heteroaromatic compounds from the R P L C is expected to be difficult because hydrogen-bonding factors of the heteroatoms are sensitive to the variations in the mobile-phase solvent composition. To solve this problem, we thought that systematic analyses of log k ' values measured with various mobile-phase compositions would be necessary. Previously (9,10), we have analyzed relationships among log Ρ values of substituted benzenes, pyridines, and diazines measured in various partitioning systems. In this chapter, we first describe briefly the analysis of the relationship between log Ρ and log PQL for monosubstituted pyridines and pyrazines. Then, we extend our procedure for the analysis to the relationship between log Ρ and log k values measured under various conditions for various series of heteroaromatic compounds. Finally, to obtain reliable log Ρ value of heteroaromatic compounds having various substituents, a new hydrogen-accepting scale of substituents, S HA, defined on the basis of the heat of formation under various dielectric environments, is proposed. Our emphasis is placed upon finding optimal RPLC conditions for estimating "accurate" log Ρ values. 1

Methods

Partition Coefficients : The log Ρ values for newly measured compounds were at 25°C by the conventional shake-flask method. Others were from literature (2,3,5,11). R P L C Procedure : A Shimadzu LC9A liquid chromatograph equipped with SPD6AV U V (Shimadzu) and SE-31 refractive index (Shoden) detectors was used. A commercial Capcell PakCis (4.6 mm χ 15 cm, Shiseido) was used without further treatment. The MeOH-phosphate buffer (pH 7.4) eluents were prepared by volume. Retention times were measured using a C-R4A Chromatopac (Shimadzu). The capacity factor, k\ was determined from the retention time of each sample, ÎR, and that of methanol, to, as k* = (ÎR - to) I to . The log k value at 0% MeOH, log kw was calculated by the linear extrapolation from the plot of log k values against methanol concentrations ranging from 30 to 70% (12). 1

y

1

^ HA Parameters : A parameter, S HA, representing the propensity of a certain substituted compound to be stabilized with being surrounded by dielectric media such as solvents relative to that of the unsubstituted compound was defined here for various substituents in various (hetero)aromatic systems. Thus, the S HA value is a substituent constant specific to each of the skeletal systems. First, the minimum energy conformations of each compound in the gaseous state were calculated using the A M I method (13) in the M O P A C 93 program package incorporated in an A N C H O R II modeling system (Fujitsu) (14). Then, using the minimum energy conformation in the gaseous state as the initial geometry, the conformational optimization and the calculation of the heat of formation in various solvents were made with use of the COSMO (conductorlike screening model) method (15) which approximates the effects of solvent molecules surrounding the molecule in question with the eps (ε: dielectric constant) command. Thus, the heat of formation (Hj) values in the gaseous state (ε = 1), chloroform (4.8), octanol (10.3), methanol (32.7) and water (78.4) were obtained for each compound. When the Hf values calculated for five dielectric environments of each substituted compound (ArX) were plotted against the corresponding Hf values for the unsubstituted parent compound (ArH), a straight line was drawn as shown in Figure 1. The slope of this line was defined asS/f^As observed, the higher the dielectric constant of the medium, the more negative the Hf value so that the greater the stabi-

Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

38

CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY

lization induced by solvation with dipolar solvent molecules. As the X-substituents, either non-hydrogen bonding or hydrogen-accepting groups were used. Except for the gaseous condition as the reference state, the solvents examined were either hydrogendonor or amphiprotic. Therefore, the S HA parameter is expected to reflect the hydrogen-accepting propensity of the substituent X relative to H in a given series. -30

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//^(X=COOMe) -35 /

ε=1

-40-1

-45 H ε=4.8 ε=10.3

-50 A

Jr ε=32.7 ' ε=78.4

-5532.5

35

H (X=H) f

37.5

40

42.5

45

Figure 1. Plot of the Hf Values for a Substituted Pyrazine (X = COOMe) against Those for the Unsubstituted Pyrazine (X = H) Calculated under Various Dielectric Environments. Results and Discussion

Relationship between log Ρ and log PCL ' Previously, we have shown that the relationship between log Ρ and log PCL f ° disubstituted benzenes (X-C6H4-Y), where X and Y are variable and fixed substituents, respectively, is expressed in general as equation 1 (9). r

log^CL = a log P^ + hHB + ρσ° + const.

(1)

In equation 1, the parameter σ° is the electronic substituent constant of the X substituents free from the through-resonance effect. HB is an indicator variable which takes unity for Η-accepting substituents X (for example, OR, A c , C N , NMe2, NO2, and CONMe2) and zero for non-hydrogen-bonding substituents (alkyls and halogens). Amphiprotic X-substituents are not included here because they usually show various degrees of the deviation from the regression line for non-hydrogen-bonders depending on the hydrogen-donating association of X-substituents with 1-octanol. The values a, h and p are regression coefficients. The value of "a" is close to unity. The ρσ° term, when statistically significant, represents the electronic effect of X on the hydrogenbonding solvation of the Y-functional group with CHCI3 relative to that with 1-octanol. The HB term expresses the hydrogen-accepting effect of the hydrogen-accepting substituents at the substituent site. Usually, the h value is near 0.3. From detailed analyses (9), this value has been shown to correspond approximately to the logarithm of the ratio of the bulk solvent molality between C H C I 3 and octanol. The fact that the

Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

3. YAMAGAMI & FUJITA

Hydrophobicity of Heteroaromatic Compounds39

discrete-type indicator variable, HB, works well suggests that the hydrogen-bonding equilibrium is almost entirely in favor of the bonded state for above HB substituents and the hydrogen-accepting equilibrium constant of these substituents in C H C I 3 is almost proportional or equivalent to that in octanol at least in conventional disubstituted benzene series. Equation 1 has been applied to heteroaromatic compounds by regarding the ring hetero-atom(s) as the Y substituent(s) (10). Thus, the analysis for a-monosubstituted pyridines has produced equation 2. Downloaded by UNIV OF MASSACHUSETTS AMHERST on June 1, 2018 | https://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0606.ch003

log PCL = 1.04 log Ρ + 0.32HB + 0.42σ° + 0.56

(2)

η = 15, r = 0.991, s = 0.092 In this equation and throughout this chapter, η is the number of compounds used for calculations, r is the correlation coefficient, and s is the standard deviation. In the case of monosubstituted pyrazines, a correlation as shown by equation 3 has been formulated (10). log P L C

= 1.14 log Ρ + 0.31HB + 0.81

(3)

η = 15, r = 0.995, s = 0.067 In equations 2 and 3, the substituents used are alkyl, halogens, OR, SR, N M e 2 , C N , Ac, CO2R, and C O N M e 2 . Among them, the substituents, C O 2 R and C O N M e 2 , were treated as substituents taking the HB value of two because they have two hydrogenaccepting sites. Moreover, in equation 3 but not in equation 2, weak hydrogenacceptors such as OR, SR and N M e 2 were dealt with as if they are non-hydrogenbonders (HB = 0), otherwise the correlation would be much poorer. This treatment is reasonable considering that the electron-withdrawing two ring TV-atoms greatly decrease the hydrogen-accepting ability of such substituents in substituted pyrazines. Relationship between log Ρ and log fc' : Most RPLC procedures have used a combination of the ODS stationary phase with the methanol-water mobile phase (6,7). From log k values for a set of compounds, the non-measured log Ρ value of a compound is estimated on the assumption that the log Ρ value is linearly correlated to the log k '. This method is effective in cases when the solutes are congeneric and share a common hydrogen-bonding pattern. One of the problems in dealing with the RPLC procedure is that the log k value itself and the correlation with the log Ρ value vary with the methanol content of the mobile phases. To eliminate the effect of the methanol composition, many investigators have conventionally used the log lew value which is the extrapolated log k ' value to the 0% methanol (6,7). In fact, this log kw parameter is a direct indicator of log Ρ for certain compounds which have no polar functional groups. However, we have found this approach ineffective in cases when hydrogen-bonding polar ring-hetero atoms and substituents are included in compounds. First, we show the case of monosubstituted benzenes as the reference. In Figure 2, log kw values are plotted against log P. Compounds with most nonhydrogen-bonding and "weakly" hydrogen-bonding substituents fit a single straight line of log kw = log Ρ meaning that, for these compounds, the log kw value can be a direct indicator of the log P. However, carbonyl hydrogen-acceptors such as ester and acetyl substituents, gave a log kw value about 0.3 higher than log P. In contrast, the amphiprotic phenol showed a lower log kw value. Next, heteroaromatic compounds in Table I were examined (16). They were categorized into three groups. The log kw value for the group A compounds agreed well with log P. The log kw value for the group Β compounds was much larger than the log Ρ value. On the other hand, for the group C compounds, the log kw value was lower than the log Ρ value. Group A compounds consist of aromatic rings with non1

1

Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY

Figure 2. Relationship between log Ρ and log kw for Monosubstituted Benzenes. Closed circles : Nonhydrogen-bonders and "weak" hydrogen-acceptors, Open circles : Carbonyl hydrogen-acceptors, Closed triangles : Amphiprotics, and Open triangles : Amphiprotics having carbonyl. hydrogen-bonding or very weakly hydrogen-accepting sites, group Β compounds include heteroaromatic rings containing more than two hydrogen-accepting sites, and group C compounds contain a hydrogen donor. The above results for benzenoid and heteroaromatic compounds indicate that if we estimate log Ρ value directly from the log kw value on the assumption of the simple linear relationship, the value of hydrogenacceptors tends to be overestimated and that of hydrogen-donors underestimated. The important point, when using the RPLC method to estimate log P, is to find the optimal RPLC conditions that minimize the difference in the hydrogen-bonding factors from those involved in the 1-octanol/water system to produce a linear relationship between log Ρ and log k as far as possible. Keeping this in mind, we studied systematically the log k value of (hetero)aromatic compounds. When the relationship between log k and log Ρ of monosubstituted benzenes was examined with various mobile-phase compositions (at 15, 30, 50, 70 and 80% MeOH concentrations), the eluent containing 50% methanol, M50, gave the best linear relationship, where most substituents, except for amphiprotic substituents including OH, fell on the same straight line as shown in Figure 3. Although some amphiprotic solutes were failed to be lined up with others, we can conclude that M50 is the best eluent for estimating log Ρ values for the monosubstituted benzene system. The log k values for heteroaromatic compounds and their alkylated derivatives included in Table I were plotted against log Ρ in Figure 4. Interestingly, here again, the M50 eluent gives the best linear relationship, although group C hydrogen-donors deviate downward. In water-rich eluents, the group Β strong hydrogen-acceptors deviate upward to form a second straight line parallel to that for the non-hydrogen bonders. Similar hydrogen bonding effects were observed in correlations between log Ρ and log k for monosubstituted heteroaromatic series. In Figure 5, log k values of monosubstituted pyrazines are plotted against the log Ρ values (7 7). Also in this case, non-hydrogen bonders and hydrogen-acceptors are plotted as a single linear relationship 1

1

1

1

1

x

Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

3. YAMAGAMI & FUJITA

Hydrophobicity of Heteroaromatic Compounds41

Table I. Log Ρ and log k\y Values of Heteroaromatic Compounds*

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Ab

log kw

log F

PhH Me-Ph Et-Ph FR 2-Me-FR 2-Et-FR 2,5-di-Me-FR

2.01 2.62 3.20 1.19 1.80 2.42 2.35

2.13 2.69 3.15 1.34 1.85 2.40 2.24

Group A -0.12 -0.07 0.05 -0.15 -0.05 0.11 0.11

PR Me-PR Et-PR PM 2-Me-PM 4-Me-PM 5-Me-PM

0.09 0.51 1.00 -0.06 0.29 0.38 0.43

-0.26 0.21 0.69 -0.44 -0.05 -0.05 0.01

Group Β 0.35 0.30 0.31 0.38 0.34 0.43 0.42

0.55 1.42 1.33 1.94

0.75 1.59 1.47 2.14

Compound

Pyr 2-Et-Pyr 2,5-di-Me-Pyr In a

Compound log kw

log F

BF 1-Me-Pyr 1-Me-In TH 2-Me-TH 3-Me-TH 2-Et-TH

2.70 1.17 2.65 1.68 2.32 2.29 2.91

2.67 1.15 2.64 1.81 2.33 2.34 2.87

0.03 0.02 0.01 -0.13 -0.01 -0.05 0.04

PD 3-Me-PD 4~Me-PD QZ QX 3-Me-TA 3-Ph-TA

-0.33 0.09 0.22 1.22 1.51 -0.24 2.03

-0.73 -0.35 -0.32 0.90 1.32 -0.55 1.71

0.40 0.44 0.54 0.32 0.19 0.31 0.32

2.35 2.52 2.49

2.53 2.80 2.68

-0.18 -0.28 -0.19

Group C 2-Me-In -0.20 3-Me-In -0.17 5-Me-In -0.14 -0.20

Adapted from ref. 16. Abbreviations are as follows:

Η

Η

Difference between log kw and log P. with the M50 eluent. However, as the methanol concentration in the mobile phase is decreased, strong hydrogen-acceptors such as ester and N, N-dimethylamide groups deviate upward and the relationship becomes more complicated. The amphiprotic substituents deviate downward. For monosubstituted furans and benzofurans, the log k ' - log Ρ plots are shown in Figure 6 (18). Here, we used alkyl groups, ester ( C O 2 R ) and dimethyl amide ( C O N M e 2 ) groups, and amide groups (CONHR) as representatives of nonhydrogen-bonding, hydrogen-accepting, and amphiprotic substituents, respectively. In Figure 6, esters and dimethylamide together with non-hydrogen-bonders give a single linear relationship at M50, while the amphiprotic amide groups form a separate lower line with almost the same slope, the relationship being similar to Figure 5 for substituted pyrazines. The esters deviate upward with the decrease in the methanol content in the mobile phase. We tried to analyze quantitatively the results described above and to derive correlation equations between log Ρ and log k ' at each eluent composition. Among various combinations of electronic constants and indicator variables to express the Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY

I 1 1 1 1—' I 1 1 1 r - 1 0 1 2 3 - 1 0 1 2 3 Figure 4. Relationship between log Ρ and log k Values for Hetero­ aromatic Compounds. Circles : Group A Compounds, Squares : Group Β Compounds, and Triangles : Group C Compounds. Open symbols refer to benzo-derivatives. See Table I. (Adapted from ref. 16.) x

Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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3. YAMAGAMI & FUJITA

- 1 0

Hydrophobicity of Heteroaromatic Compounds43

1

2

-

1

0

1

2

1

Figure 5. Relationship between log Ρ and log k for Monosubstituted Pyrazines. Symbols for substituents are the same as those in Figure 2. (Adapted from ref. 77.)

1

hydrogen-bonding effects, we found that the log k value of a series of compounds having variable substituents X can be described by the following general equation. 1

log k = a log Ρ + ΙΪΑΗΒΑ

+ ρσι + ΥΙ^ΜΗΒΑΜ

+ const.

(4)

Here, o\ represents inductive-electronic substituent constant of substituents (79). The HBA and HBA^are indicator variables for strongly hydrogen-accepting and amphi­ protic X-substituents, respectively, which take the value of unity. The ester and Ν, Ndimethylamide substituents are classified into the HB& category, while weak hydrogenacceptors are classified as if they are either nonhydrogen-bonders or hydrogenacceptors depending on the parent nucleus. The HB term functions as a correction for the hydrogen-bonding at the substituent site and the o\ term works to represent the electronic effect of the substituents on the hydrogen-bonding of the ring hetero-atoms. The correlations derived by equation 4 for monosubstituted pyrazines are given in Table II for the same data as those in Figure 5 (77). Very good correlations were obtained in every eluent composition. The contribution of the HB& term is more important as the methanol concentration is decreased. The o\ term seems to be needed only when the ring hetero atom is considerably hydrogen-bondable as in the case of pyrazine. The hAM values are always negative, indicating that the amphiprotics are more "hydrophobic" in octanol-water partitioning system than in the chromatographic partitioning system. This is not unexpected if we consider that the amphiprotic substituents prefer to form the hydrogen-bond as a hydrogen-donor with the more "basic" octanol than the stationary phase. The variations in the size of coefficient of each term with the eluent compositions in correlations obtained using equation 4 exhibited similar tendencies in other systems. Among them, the correlations for the M50 eluent are summarized in Table III. Irrespective of the skeletal structure of the unsubstituted compounds, the HBA and σι terms were almost insignificant with the M50 eluent. Moreover, the coefficients "a" of the log Ρ term are very close to each other, being 0.61 ± 0.04. This suggests that the contribution of the "hydrophobicity (in terms of the 1-octanol-water Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

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CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY

Figure 6. Relationship between log Ρ and log k ' for Monosubstitutedbenzenes, -furans, and -benzofurans. Substituents are as follows. Closed circles : Η and alkyl, Open circles : C O 2 R and C O N M e 2 , Triangles : C O N H 2 and CONHR. Table II. Correlations for Monosubstituted Pyrazines according to Equation 4 a

Buent M15 M30 M50 M70

b

a 0.824 0.744 0.582 0.495

h

A

0.414 0.237

Ρ -0.371

hAM

const.

η

r

s

-0.319 -0.305 -0.349 -0.348

0.292 -0.147 -0.511 -0.887

19 19 19 17

0.991 0.996 0.992 0.991

0.078 0.050 0.060 0.051

a

Adapted from ref.77. Substituents included, Non-hydrogen-bonders : H , alkyls, F and CI, "Weak" hydrogen-acceptors : OR, SMe, N M e 2 , Ac, and C N , "Strong" or carbonyl hydrogen-acceptors : COOR and C O N M e 2 , and Amphiprotics : N H 2 , NHMe, NHAc, and C O N H 2 . The figure represents the MeOH % contained in the mobile phase. b

system)" to the capacity factor can be separated from other factors by the simple treatment formulated as equation 4. Another point to be noted is that the hA M value for heteroaromatic systems is more negative than that for the benzenoid systems (PhX and BC). This is probably because the electron-withdrawing property of the endocyclic hetero-atom(s) increases the hydrogen-donating ability of amphiprotic substituents in heteroaromatics. The above results demonstrate that log k values obtained with the eluent containing 50% MeOH are usually correlated with log Ρ by a single linear relationship as long as amphiprotic substituents are treated separately. It should be noted here that the behaviors of amphiprotics represented by a single indicator variable ΗΒΑΜΪΩ Tables II and III are because the variety of amphiprotic substituents is limited %

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3. YAMAGAMI & FUJITA

Hydrophobicity of Heteroaromatic Compounds

45

Table III. Correlations Obtained by Equation 4 with the M50 Eluent Series a

PR 5PM FR TH PhXf BCS d

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e

b

a

h

0.582 0.614 0.635 0.620 0.652 0.581

AM

const.

η

r

s

-0.349 -0.380 -0.195 -0.254 -0.118 -0.067

-0.511 -0.423 -0.544 -0.644 -0.608 -0.508

19 14 18 27 18 19

0.992 0.999 0.999 0.996 0.997 0.998

0.060 0.024 0.022 0.055 0.042 0.028

n A

0.103

c

a

Monosubst. pyrazine, for substituents included, see footnote a of Table II (ref. 77). 5-Subst. pyrimidine, Non-hydrogen-bonders : H , alkyl, and halogen, "Weak" hydrogen-acceptors : OR, C N , and N O 2 , "Strong" hydrogen-acceptors : C O 2 R , and Amphiprotics : N H 2 , NHAc, and C O N H (ref. 20). HB was used only for C O 2 R . 2- and 3- Subst. furans, Non-hydrogen-bonders : H and alkyl, "Weak" hydrogenacceptors : OR and C N , "Strong" hydrogen-acceptors : C O 2 R , and Amphiprotics : CONHR (ref. 27). 2 - and 3- Subst. thiophenes, Non-hydrogen-bonders : H , alkyl, and halogen, "Weak" hydrogen-acceptors : OR, C N , A c , and NO2, "Strong" hydrogen-acceptors : C O 2 R , and Amphiprotics : CONHR. Monosubstituted benzenes, Non-hydrogen-bonders : H , alkyl, halogen, and CF3, "Weak" hydrogen-acceptors : OR, SMe, C N , and N O 2 , "Strong" hydrogen-acceptors or carbonyl hydrogenacceptors : C O 2 R and A c , and Amphiprotics : N H A c and C O N H 2 . S m- and psubstituted benzyl N, N-dimethylcarbamates, Non-hydrogen-bonders : H , alkyl, and halogen, "Weak" hydrogen-acceptors : OR, SMe, N M e 2 , and N O 2 , "Strong" hydrogen-acceptors : C O 2 R , and Amphiprotics : CONHR, NHAc, and NH2. (ref. 77).

b

C

2

A

d

e

f

within CONHR, N H A c , and NHR (R : alkyl and H). With broader amphiprotic substituent species such as OH and COOH, more than a single indicator variable should be required (9). Hydrogen-acceptor Scale : In above analyses, discrete-type indicator variables worked well for expressing hydrogen-bonding effects. As described above, however, the assignment of the value of zero or unity to the HBA parameter is sometimes not explicitly preestablished, but dependent upon the (hetero)aromatic skeletal structure. Therefore, the utilization of the preestablished individual hydrogen-bonding parameter for each substituent was considered to be relevant. The S HA value calculated for substituents X in various series of A r X (see Methods) was expected to be such a parameter. By definition, the S HA value of H in any skeletal series is unity, and the higher the value for X , the higher the hydrogen-accepting propensity of the substituent X in a given skeletal series. In Table IV, the SHA value of fundamental substituents for monosubstituted pyrazines is given together with those for monosubstituted benzenes. Generally speaking, non-hydrogen-bonding and very weakly hydrogen-accepting substituents have the value near unity, and stronger hydrogen-accepting substituents have larger values. It is of interest to notice that substituents such as N M e 2 and OMe in the pyrazine series, which behave as non-hydrogen-bonders, have a SHA value near unity, whereas the same substituents in the monosubstituted benzene series, which behave as hydrogen-acceptors, have a fairly large SHA value. We thought that the SHA parameter could be a good indicator of hydrogen accepting ability as a first approximation. Thus, we re-analyzed our experimental data using this parameter. Regression analyses were made by replacing HBA with SHA and Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

46

CLASSICAL AND THREE-DIMENSIONAL QSAR IN AGROCHEMISTRY

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Table IV. SHA Parameter Value of Typical Substituents

a

a

Substituent

PhX

PR-X

F Cl Me (Me SMe CN NMe2 Ac C02Me CONMe

1.15 1.13 1.03 1.92 2.13 1.98 2.00 2.82 2.96 3.69

0.99 0.97 0.96 1.02 0.95 1.21 1.09 1.31 1.64 1.68

2

Substituted pyrazines.

excluding the amphiprotic substituents from calculations. The results for monosubstituted pyrazines are given below. The relationship between log Ρ and log PCL shown by equation 5 was much improved by adding the SHA giving equation 6 as the counterpart of equation 3. t e r r n

log PCL = 1 · 143 log Ρ + 0.855 n= 15, r = 0.922, s = 0.254

(5)

log^CL= 1.H3 log/>+ 1.0775//Λ -0.231 n= 15, r = 0.993, s = 0.080

(6) %

Similar analyses for the relationship between log Ρ and log k were performed using equation 7. log k ' = a log Ρ + SSHA + P ^ i + const.

(7)

The results given in Table V shows that excellent correlations can be obtained at every mobile-phase composition. The quality of correlations found in equation 6 and those in Table V is excellent, but almost equivalent to that of their counterparts using HB in equation 3 and Table II. In spite of the fact that the SHA value is not available for the amphiprotic substituents, the use of the SHA variable is advantageous because of no arbitrariness in this calculable parameter. Table V. Correlations for Monosubstituted Pyrazines according to Equation 7

Buent M15 M30 M50 M70

a

a 0.866 0.769 0.581 0.489

s 0.804 0.448

Ρ -0.472 -0.208

const.

η

r

s

-0.551 -0.575 -0.511 -0.884

15 15 15 14

0.997 0.998 0.990 0.986

0.042 0.034 0.059 0.052

The figure represents the MeOH % contained in the mobile phase. Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.

Downloaded by UNIV OF MASSACHUSETTS AMHERST on June 1, 2018 | https://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0606.ch003

3. YAMAGAMI & FUJITA

Hydrophobicity of Heteroaromatic Compounds

47

The SHA value calculated with the MNDO-PM3 hamiltonian was also tried, but the correlations were inferior in all the cases studied. Although semi-empirical calculations have limitations in their utility, the above results indicate that our new parameter is justifiable for expressing the hydrogen-accepting ability of substituents. Further investigation with a larger number of compounds will be needed to show its versatility. It should be noted that the SHA parameter is ineffective in dealing with hydrogen donors or amphiprotics, and an effective method of treating hydrogendonors is still to be found. In this chapter, we showed how hydrophobicity parameters derived from different partitioning systems are correlated with their octanol-water log Ρ values. Even if relationships seem complicated, they can be analyzed by using appropriate "correction" terms for hydrogen-bonding behaviors. Our analyses showed that in predicting log Ρ values by RPLC, the use of eluents containing around 50% methanol seems to be more practical than the conventional log kw approach. Especially in heteroaromatic systems, solutes with amphiprotic (Η-donor) substituents yielded significant deviations from the regression lines for non-hydrogen bonders, and hence should be treated carefully. Literature

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Cited.

Hansch, C.; Fujita, T. J. Am. Chem. Soc. 1964, 86, 1616. Hansch, C.; Leo, Α.; Hoekman, D. Exploring QSAR ; American Chemical Society: Washington, D.C., 1995; Vol. 2. Yamagami, C.; Takao, N.; Fujita, T. Quant. Struct.-Act. Relat. 1990, 9, 313 and the references cited therein. Yamagami, C.; Takao, N.; Fujita, T. J. Pharm. Sci. 1991, 80, 772. Bradshaw, J.; Taylor, P. J. Quant. Struct.-Act. Relat. 1989, 8, 279 and the references cited therein. Braumann, T. J. Chromatogr. 1986, 373, 191. Minick, D. J.; Frenz, J. H.; Patrick, Μ. Α.; Brent, D.A. J. Med. Chem. 1988, 31, 1923 Terada, H. Quant. Struct.-Act. Relat. 1986, 5, 81. Fujita, T.; Nishioka, T.; Nakajima, M. J. Med. Chem. 1977, 20, 1071. Yamagami, C.; Takao, N.; Fujita, T. J. Pharm. Sci. 1993, 82, 155. Yamagami, C.; Takao, N. Chem. Pharm. Bull. 1993, 41, 694. Yamagami, C.; Takao, N. Chem. Express 1991, 6, 113. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am.Chem. Soc. 1985, 107, 3902. Stewart, J. J. P.; Fujitsu Ltd., Tokyo. Kamlet, Α.; Shüürmann, G. J. Chem. Soc., Perkin Trans. 2, 1993, 799. Yamagami, C.; Takao, N. Chem. Express 1992, 7, 385. Yamagami, C.; Ogura, T.; Takao, N. J. Chromatogr. 1990, 514, 123. Yamagami, C.; Yokota, M.; Takao, N. J. Chromatogr. 1994, 662, 49. Charton, M. Prog. Phys. Org. Chem. 1981, 13, 119. Yamagami, C.; Yokota, M.; Takao, N. Chem. Pharm. Bull. 1994, 42, 901. Yamagami, C.; Takao, N. Chem. Pharm. Bull. 1992, 40, 925.

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Hansch and Fujita; Classical and Three-Dimensional QSAR in Agrochemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1995.