A r o m a t i c S u b s t i t u e n t Constants
JournaI of Medicinai Chemlstri 197.? \b/ 16 .Yo 11 1207
“Aromatic” Substituent Constants for Structure-Activity Correlations? Corwin Hansch,* Albert Leo, Stefan H. Unger, Ki Hwan Kim, Donald Xikaitani, and Eric J. Lien D e p a r t m e n t of C h e m i s t y , Pomona College, Claremont, California 91 711 Receiced J u n e 18, 1973 Aromatic substituent constants (lipophilic T , electronic um a n d u,>. and steric MR, molar refractivity) have been collected for 236 substituents including 128 7r values and 191 values for which both u,,, and cr,] were found. Swain and Lupton’s 3 and cR values could then be calculated for these 191 substituents by a corrected procedure. The mutual correlation of u,,, and g,] is high, r = 0.903. while 5 and C are essentially orthogonal.
Interest in the use of substituent constants for correlating structure with reactivity continues to grow rapidly in both simple organic1 as well as complex biochemical2 and biomedicinalsa-d systems. The use of cr constants (Hammett and Taft) for the electronic and E, constants (Taft3e) for the steric effects of substituents has greatly facilitated understanding of organic reaction mechanisms.1.3e.4 The hydrophobic parameters5 a and log P have bridged the gap between simple organic and biochemicalbiomedicinal systems. To further advance the extrathermodynamic approach4b to quantitative structure-activity relationships (QSAR),3a-d we have made a search of the literature to assemble as many substituents as possible for which both um and uu have been determined. These appear in Table I together with measured T values and other parameters calculated as described below. There are two reasons for focusing on these two particular electronic parameters6 instead of any of the others. First, far more of these constants are available than others such as u I or u R . 7 Second, it is possible, using only om and up! to factor the electronic effect into resonance and nonresonance components.6 Since Taft and Lewis7 first explored factoring of this kind, it has become increasingly evident that it can lead t o greater insight into substituent effects. Although there are a variety of ways in which such factoring can be accomplished,6-8s$the general approach of Swain and Lupton6 has the advantage that 3 and (R can be calculated directly from crm and up, avoiding nongenera1 procedures.8.f A further improvement by way of an optimization-orthonormalization procedure will be published shortly.$ This modification has the advantage of depending upon a large amount of data instead of an “arbitrarily” selected model reaction(s); it contains only a single general chemical constraint and it guarantees completely independent (orthogonal) and equiscalar (normal) substituent vectors. Actually, 5 and CR are remarkably orthogonal, as will be discussed below, and therefore they largely avoid the common pitfall of multicollinearity (even though they are neither “optimum” nor precisely orthogonal). To provide a measure of hydrophobic character, Table I lists the known5b values of T from the benzene solute system partitioning in the octanol-water soluent system and also includes many new x values not previously reported. T constants have previously been measured using a variety of solute systems.§ The most common “parent” solutes tThis work was supported by Grant CA 11110 from the National Institutes of Health and in part by Contract DRR-70-4115 from the National Institutes of Health. :C. G . Swain, S. H. Unger, P. Strong, and N . R. Rosenquist, unpublished results. §To avoid confusion in use of the term “system” in partitioning studies, the following symbolism will be followed in this and subsequent papers from this laboratory. (11 K or log P is followed by a dash and the formula for the substituent or the solute, respectively. For li values, the substituent formula can be followed by a slash ( / ) and then the solute name or formula. (21 The solvent system is given in parentheses following the solute, but only the organic phase need be specified. If no solvent is specified, it is assumed to be octanol-water. For example, a-4-Cl/phenol (oleyl alcohol) = 0.82 refers to the K value for the chloro substituent in the para position from the phenol solute system measured in oleyl alcohol-water.
(besides benzene) on which the substituents are placed are phenol, phenoxyacetic acid, benzoic acid, aniline. and nitrobenzene. The variation from system to system can often be predicted with acceptable precision.5a and it is generally not so great that it precludes using the s constants from benzene to serve in the design of new drugs and enzyme substrates where the variable substituent is attached to any aromatic ring. The s-/benzene values are much more independent of electronic contributions than. say, a-/nitrobenzene and are thus more likely to represent a true “lipophilicity” for aromatic substituents. Where the attachment is at an aliphatic site, the substituent a constant from benzene requires a correction for electronic effects and possibly for “folding” over the ring.5b Additivity of both P and u on benzene rings is considered below. The most widely used parameter for steric substituent effects in organic reaction mechanism studies is Es.3e This parameter is useful for studying intramolecular steric effects, particularly in reactions where the substituent is near the reaction center. However, since E , constants have not been determined for the majority of substituents listed in Table I and since biochemical-biomedical “steric” requirements are often (but not always) of the “bulk” type, we have sought another measure, albeit approximate, of the general “steric” bulk. Fortunately, there are two parameters which are readily available for each substituent: molar refraction (MR) and molecular weight (MW). Van der Waals molar volumes as calculated by Bondis might also have been used but. for the full range of substituents listed in Table I, a great number of approximations and assumptions would have been necessary. MR values have been used previously in some biological QSAR.lO For liquids, the MR can be calculated (in units of volume) from the Lorentz-Lorentz relation=
MR =
~
~
(
-1 1 ) 2/ d ( ~n 2 + 2 )
(cm3/mol) ( I )
where MW = molecular weight, n = index of refraction (normally a t 20”, Na D line), and d = density (normally a t 20”). The tolerance by enzymes and receptors for the “bulkiness” of the substrates and drugs to which they are exposed is a problem of great concernll in biomedicinal-biochemical studies. We believe that MR and/or M W may be crude but useful measures of “bulk.” W e uish to e m phasize, howecer, that we consider these parameters as only a possible interim solution. M R contains an electronic contribution (it is directly proportional to the polarirability); therefore, its use in multiple regression analysis m u s t be ciezoed with caution. The MR values in Table I were included partly for the purpose of the cluster analysis which appears in the following paper.12 In this they are somewhat less critical than in a multiple regression. Methods
1. Hydrophobic Parameters. Log P values have been determined as previously d e ~ c r i b e d . ~Ina general, at least =References to MR are found in Table I, footnote d
N=191
R4.903
5 ~ 0 . 1 7 Um = - O . l l (0.03)+1.2310.OB)r up
,/
/
/”
I’
R .I ‘-a.m
-11.2
-0.a
U.GY
0.32
vm
u.611
u. w
d
1.16
I.
YV
1.77
2. m
Figure 1. Plot of oln ~ ‘ 6 b. y ,for 191 substituents
four determinations of P have been made a t varying concentrations. Where P is a function of concentration, we have extrapolated to infinite dilution. We have used the value of 2.13 for log P-benzene. BoCek and Tichj.** have obtained a value of 2.15. In a few instances, as noted, r-X/benzenec was not available, and a constant from another solute system was given. Ionic substituents, such as - C O z - and -?jMes+, are so hydrophilic that, when a t tached to benzene, the resulting log P is so low t h a t it is quite difficult to measure. In such cases, the more lipophilic biphenyl solute system was used. 2. Electronic Parameters. un, and g P values were taken from our larger (unpublished) collection of substituent constantstt a n d represent both primary and secondary values of varying quality. We have attempted to select the “best” values available for each substituent, using updated values and discarding inconsistent values. However, we urge that the original sources be consulted because of the variety of methods represented. We have completely repeated Swain and Lupton’s procedure for obtaining 5 and @ since the factor p = 1.65 was omitted from the calculation of u’ (ionization of 4-X-bicyclooctanecarboxylic acids in 50 wt % E t O H , Set 5 ) 6 with the effect that their 5 values are out of scale w i t h a . Furthermore, our selected um and up do not always agree with those of Swain and Lupton. We have consistently rounded to two decimal places, and our 5 and (R are selfconsistent with the url,and up in Table I. Thus **M. Tich? and K. BoEek, private communication. ttPomona College Medicinal Chemistry Project, Claremont, Calif 91711.
5
=
1.369 (i0.186) 0.009 (i0.038)
- 0.373 (h0.142) iI
1-
1 4 0.9915
C J ~-
S
0.0417 (2)
The figures in parentheses are 95% confidence limits; the overall F statistic if F2.11 = 318.77 ( F z , l l . a = ~ . 0 0 5 = 8.91). All the coefficients are evaluated from 14 data points of Baker, et al 13 (corrected for p = 1.65), but all 5 are calculated from eq 2 . Then
@==oa,-cYr7
(31
which gives CY = 0.921 under the assumption6 that R ( X M e 3 t ) = 0.0 ( u p = 0.82, 5 = 0.89). Independent evaluation of new substituent constants has confirmed the general validity of this assumption.8,; Results given below further show that 5 and 6l are remarkably orthogonal. considering the relative simplicity of the assumptions. 3. Steric Parameters. There are various systems for calculating molar refractivity, but the atom-group-structure constants of Vogel and the bond values of Vogel and others= are the ones most commonly used. The atomgroup-structure system of Vogel could be applied to the greatest number of substituent structures of Table I, and so it was chosen for the sake of consistency. However, exaltations between aliphatic and aromatic values can be rather large (as much as lo%), and for substituents containing unsaturation or a lone electron pair which could interact with the benzene ring, and for which Vogel did not list separate aromatic values, we have used Ingold’s special values. We have ignored the slight variation
Aromatic Substituent Constants
Journal ofhfedicinal Chemistry, 1973, Vol. 16, No. 11 1209
Table I. “Aromatic” Substituent Constants No.
Functions
bm
?Th
UP
Y
at 0.18 -0.17 0.04 0.05 0.19 0.19 0.13 0.13 0.15 0.05 0.03 0.03 0.14 -0.13
MRd
MWe
Wiswesser line notation1
Ref om
rpg
~
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 64 65 66 67 68
B (OH)2 Br CBr3
cch
CF3 CN
coo -
-0.55 0.86 0.88 -0.57 -4.36W -0.65 -0.32 0.79 0.17
CHO COOH CHtBr CHzC1 CHJ -1.49 CONHI -0.38 CH=NOH -1.87 C=O(NHOH) 0.56 CH3 -1.03 CHiOH -1.04 CHtNH, 0.02 CEO (CFa) 3,4- (CFzOCFI) C=CH 0.40 CHISCF3 CH2SOzCF3 -0.57 CHQCN CH=CHNO, 0.11 (trans) CH=CH? 0.82 COCHI -0.55 COzCH3 -0.01 CHICOOH -0.72 C=O(NHCHs) -1.27 CH?CONH? -1.68 C=S(NHCH3) 1.02 CZHB 1-(1,2-BioHiaC~H) a-carboranyl 3-Barenyl 1-Neobarenyl CECCF~ CF(CFI)? C (OH) (CF3)2 CH=CHCFI (trans) CH=CHCFa (cis) CH=CHCN -0.17j CzCCH3 CH=CHCHO CH=CHCOOH 0 .oo CHzCH=CHz 1.10 C yclopropyl CHCOCHa -0.69 CO?C?H; 0.51 CH?OC=O(CHs) -0.17 CHgCHgCOzH -0.29 3,4- (CH&H,CH?) 1.20 CHzCH(NH3+)- -3.56‘ coo CaH, 1.55 1.53 CH(CHa)? -0.15m CH?N(CH3)? CF~CF~CFZCF~ 2-T hienyl 1.61 3,4-(CH= 1.32 CHCH=CH) CH=CHCOCHs -0.06i C yclobutyl 1.39X C(CH:j), CHsSi(CH& 4-Pyridyl CH=CHCOICIH:, Cyclopentyl
1.98 0.32 0.861 2.14X
0.80 0.19 0.10 0.27 0.21 0.33
44.8 79.9 251.7 118.4 69 .O 26 .O 44 .O 29 .O 45 .O 93.9 49.5 140.9 44.0 44 .O 60 .O 15 .O 31 .O 30.1 97 .O 116 .O 25 .O 115.1 147.1 40 .O 72 .O
1 *BQQ *E 2 *XEEE 3 *XGGG 3 *XFFF 2 *CN 2 *vo 2 *VH 4 2 *VQ 1 *1E 1 *lG *11 1 *vz 4 *lUNQ 7 *VMQ *1 2 *1Q 8 *1z *VXFFF *XFFOX*FF(C,D) 9 10 *lUU1 *1SXFFF 11 *lSWXFFF 11 *1CN 1 *1UlNW -T 12
0.07 0.32 0.33
-0.08 10.99B 0.20 11.18B 0 . 1 5 12.87B
27.1 43.1 59.0 59.0 58.1 58.1 74.1 29.1 143.2
*1U1 *V1 *vo1 *1VQ *VM1 *1VZ *YUS&M1 *2 *?
5 2 13 8 14 14 15 14 14 2 2 16 16
143.2 143.2 93 .O 169 .O 167.0 95 .O
*? *? *lUUlXFFF *XFXFFFXFFF *XQXFFFXFFF * l U l X F F F -T
17 17 18 19 19 3
17 17 18 19 19 3
3
3
0.12 0.23 0.29 0.33 0.54 0.66 0 .oo 0.42 0.45 0.14 0.12 0.11 0.36 0.10
-0.07 0.44 0.27 0.31 0.38 0.51 -0.15 0.31 0.33 0.10 0.10 0.09 0.24 0.25
-0.07 0 .oo
-0.17 0.00
-0.04 0 .oo
0.81 0.21 0.12 0.29 0.16 0.32
0.81 0.23 0.15 0.31 0.01 0.26
0.05 0.38 0.37
0.30 -0.07 0.48
-0.02 0.50 0.45 -0.07 0.36 0.07 0.34 -0.15 0.52
0.27 -0.05 0.45
0.20 0.25 0.41 0.37 0.29 0.24
0.19 0.33 0.51 0.53 0.30 0.27
0.19 0.21 0.36 0.30 0.28 0.22
0.01 0.14 0.18 0.25 0.05 0.07
14.13B 13.44 15.18 15.57B
0.16
0.17
0.15
0.03
15.57B
0.24
0.17 0.09 0.13 0.90
0.26
0.35
0.24 0.14 -0.07 0.37 -0.03 -0.26 -0.07 -0.07 0.47 0.09 0.04 0.21 -0.48 -0.08 -0.10 -0.16 0.19
-0.21 0.45 0.05 -0.07 -0.26 -0.13 -0.15 0.01 0.52 0.05 0.04 -0.01 -0.15 -0.48 -0.16 -0.20 -0.21 0.03
- 0.02
1 2 3 3 2 2 2 5 2 1
11.04Ah 8.88B 28.81 20.12 5.02 6.33B 6.05BC 6.88B 6.93B 13.39 10.49 18.60 9.81B 10.28B 11 .22B -0.13 5.65 0.00 7.19 9.09 11.17B 0.08 10.19 0.05 9.55B 0.06 17.59 0.06 17.51% - 0 . 1 8 10.11 -0.05 16.42B
-0.01 0.39 0.28 0.32 0.43 0.56 -0.10 0.35 0.37 0.12 0.11 0.10 0.28 0.22
0.34
11.88 0 . 0 5 14.57B 14.41 0 . 0 9 22.33 - 0 . 1 0 10.30 0.10
-0.02 -0.27
16.23B 14.14B - 0 . 1 2 16.88B 1 . 0 4 17.91Bk 14.49 -0.19 1 3 . 5 3 15.06 0 . 1 5 17.47B 16.48 -0.05 16.52 - 0 . 0 1 13.94
-0.06 -0.05
-0.08 -0.10
0.27 -0.15 -0.03 0.33
0.44 0.10 0.03
-0.07
14.96 14.98 18.74 0 . 1 1 17.65 0.04 24.04An 0 . 0 1 17.47A0
0.28
-0.27
-0.49 -0.06 -0.07 -0.15
-0.03 -0.11 -0.13 -0.07
0.24
-0.19
21.10B 17.88 18.59 19.59 19.62 29.61D 23 .03Ae 27.21B 22.02
95 .O * l U l X F F F -C 52.1 39.1 55.1 71.1 41.1 41 . I 57.1 73.1 73.1 73.1 42.1 88.1
1 1
6 7 2 8 9 10 11 11 4 12
5 2 2
*lUlCN *1uu2 *1U1VH *lUlVQ *2u1 * AL3TJ *1v1 *v02 *1ov1 *2VQ *3*(C,D) *1YZVQ
20 20 21 21 20 20 22 8
43.1 43.1 58.1 219 .O 83.1 52.1
*3 *Y *lNl&l */XFF/ 4 F * BT5SJ R A* B*(C,D)
5 24
69.1 55.1 56.1 57.1 57.1 87.2 78.1 99.1 69.1
*lUlVl * AL4TJ *4*(C,D) *4 *X *l-SI-1&1&1 * DT6NJ *1UlVO2 * AL5TJ
20
23 23 2 22 4
2 15 22 4
4 2 25 19 19 26 26 2 2 20 27 4 4 5 4 2 2
2
20
20 27
2
1210 Journai ofMedmnal Chemlstn. 1973, Val 16, No I 1
Hansch, et a1
Table I (Continued)
No. 69 70 71 72 73 74
Functiow CiHi, (CH?)3N(CH,) 1 CsCl CeF, CsH2[2,4,6(NO?)il C6Hi
T*
61"
-0.08 0.60 0.25 0.34 0.26 1.96
0.06
0.24 0.30 0.24
MR' -0.09 24.25 28.04 0.02 49.53B 0 . 1 3 23.98B 0.08 42.21B
0.08
-0.08
Ul)
7 c
-0.15
-0.06
-0,13 0.24 0.41 0.30
-0.01
1%
0.15 76 77
Cyclohexyl 2.51X (CH?)rN(CH3)3+ - 4 . 1 5
Wiswesser line notation ' *5 *3N1&1 *R-/G 5 *R-/F 5 *R B N W D N W FNW
25.36"
7 7 . 1 *R
24.80
81.2
26.69
Ref gri,
dp"
5
29 29
5 25 29 29
1
1
2
2
* AL35TJ
27
83.2 * AL6TJ 101.2 *3K
* CT56 BN
-
27 25
0.30
0.33
0.28
0 . 0 7 32.74
118.1
DOJ
30 30
2.13
0.27
0.29
0.25
0.06
134.2 * C T 5 6 B N DSJ
30 30
1.05 -0.29 2.01 0.54
0.34 0.35
0.43 0.42 -0.09 -0.03
0.30 0.31 -0.08
78 T
-0.22 0.02
MWe 71.2 86.2 249.3 167.1 212.1
'
2-Benzoxazolyl 79
_t.yJ
2-Benzthiazolyl 80 C=O(CaH:) 81 CH=NCsH$ 82 CHlCsH5 83 CH(OH)C6H,
-0.08
0 . 1 6 30.33B 105.1 *VR 0.13 3 3 . 0 1 ~ 7 1 104.1 * l U N R - 0 . 0 1 30.01 91.1 *lR 107.1 *YQR 31.52 29.44
0.01
89 90
CsCCsH, CH=CHCsH, CHQCHQCGH; CH=CHCOC,Hd(4-NO2) CH=CHCOCsHj Ferrocenyl
91
Adamantyl
85 86 87 88
F GeBr:$ GeC1, GeFa H HgCHJ I IO IO? NO NO2 NzNf NNN NH:! NHOH NHr-111 NHNH, 112 NHS02NHSO.r NH? 113 5-C1-1-tetrazolyl
0 . 0 5 33.21B
0.12 0.06
-0.12
0.15
0.16 -0.07 -0.12 0.05
0.18
-0.11
0.951 2.46
0.18 -0.15
0.05 -0.18
0.22 -0.15
- 0 . 1 5 40.25B - 0 . 0 4 48.24AQ
3.30Y
-0.12
-0.13
-0.12
-0.02
0.14 0.03 2.66
0.17
0.21
0.15
0.36 0.37 0.34 0.66 0.71 0.85
0.56 0.23 0.06 0.73 0.79 0.97 0.00 0.10 0.18
0.27 0.41 0.43 0.62 0.67 0.79
0.78 0.12 0.78 1.91 0.15 -0.66 -0.34 0.60
0.63
l-Phenyl-2benzimidazolvl 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 10s 109 110
38.88DiJ
0.71 0.14
0 .oo
1.12 -3.74 -3.46 -0.12 -0.28 0.46 -1.23 -1.34 -0.88 -2.11a -0.65
0.41 114 N-CClr 115 N -C=O 1.15 116 N-C=S 117 5-Azido-ltetrazolyl 118 N H C N - 1.04 119 1-Tetrazolyl 120 5-OH-1-tetrazolyi 121 F. SH-1-tetrazolyl
0 .oo
0.43 0.35 0.68 0.71 1.76 0.27 -0.16 -0.04 0.86 -0.02
-0.55
0.00
0.54 0.40
0.67 1.69 0.30 0.02 0.06 0.94 0.17
*lUUlR *lUlR *2R *lIJlVR D N W
131.2 *lUlVR 185.0 * AL50J 0-FE-OL50J 135.3 * BL66 B6 A BC 1B ITJ
*VOYR&R *G *F *-GE-EEE *-GE-GGG *-GE-FFF 1 .o *H 215.6 *-HG-l 126.9 *I 142 9 *IO 158.9 *IW 30.0 *NO 46 . O *NW 28.0 *NN &J 42 . O *NNN 16 . O *Z 32 . O *MQ 17 . O *Z &H 31 . O *MZ 174.2 "MSWMSZW
0 . 3 1 60.37B 6.03B -0.15 0.92B -0.34 0 . 1 6 36.35D 0 . 1 7 25.85D 0 . 2 4 6.95D 0 .oo 1.03 -0.40 19.43D - 0 . 1 9 13.94B 39.06C' 0 . 2 0 63.51CD. 5 2 0 . 1 6 7.36' 0.36 - 0 . 1 3 10 2 B 5.42B -0.68 7.22 -0.40 -0.27 8.44 -0.71 28.40'
211.3 35.4 19 .o 312.3 178.9 129.6
0 . 0 7 23. 16Di,
103.5
0.61
0.21 0.27 0.48 0.54
0.13 0.19 0.38 0.54
0.23 0.29 0.51 0.53
-0.08
0.21 0.52 0.39 0.45
0.06
0.26 0.52 0.40 0.44
-0.18 0.02 --0.04 0.05
0.33 0.45
40.63Ar
101.1 103.1 105.2 176.2
18.35D 96.9 8.82D 42 . O 17.24D 58.1 0 . 0 5 26 .85CDr 110.1
-0.08 -0.09
10.14 18.33D" 19.77D" 26.06D3(
41 .O 69.1 85.1 101.1
1
* ATSNNNNJ
1
34
* AL36TJ
0 . 0 8 5 9 . 0 8 D ~ ~ 193.2 * C T 5 6 B N D N J BR
0.60
0.50
0.58
34.17B 34.65 45.68B
95.2
31 31 32 33
27 1
1
35 35 36 20 20 20 37
20 37
38
39
30
30
13 2 2 40 40 40 22 41 2
34 2 2 40 40 40 22 41 2
1
1
4 2 2 42 42 43 43 2 2 4 4 44 44 4 4 3
3
EG *NUYGG 3 3 *NCO 3 3 *NCS 43 43 * AT5NNNNJ 3 3 ENNN *MCN 28 28 3 * AT5NNNNJ 3 * ATSNNNNJ E$ 3 3 3 * AT5NNNNJ 3 ESH
JournalofMedicinal Chemistry, J973, Vol. 16, No. J I
Aromatic Substituent Constants
1211
Table I (Continued)
No.
123 124 125 126 127 128 129
Functiona
NHCHO NHCONH? NHCSNHz NHCHa NHSOqCHI N(CF3)s NHCOCFX
T b
-0.98 -1.30 -1.40 -0.47 -1.18 0.08
Om
UP
5c
RC
0.30
0.19
0.33
0.19 -0.03 0.22 -0.30 0.20 0.40 0.30
0.00
-0.24 0.16 -0.84 0.03 0.53 0.12
0.25 0.04 0.23 -0.11 0.25 0.34 0.36
-0.23 -0.28 -0.05 -0.74 -0.20 0.22 -0.21
0.63
0.64
0.61
0.07
MRd
MWe
Wiswesser line notation1
Ref Om
c*g
101.1 *M- ETSNNNSJ
28 28
10.31 13.72 22.19 10.33 18.17' 14.28 14.30
44.0 59.1 75.1 30.1 94.1 152 .O 112 .o
*MVH *MVZ *MYZUS *M1 *MSW1 *NXFFFXFFF *MVXFFF
43 43 28 4 43 45 43
43 43 28 2 43 45 43
49.17Dm
201.2
* AT5NNNNJ
3
3
-0.11
ESSET5MNNNJ NHCOCHzCl NHCOCHI NHCSCHs NHCzHj N(CH3)z N(SOzCH3)z N = N N (CH3)2 NHCOCzHj NHC02CzHj NHCONHCzHj NHCSNHCzH: N(CH,)C NHCOCH (CH3)z NHCH?COzC?Hs NHC4Hg N=NC sH j NHCaH, NHSOzCsHj N=CHCsHj NHCOCsH, N=NC sH3(2-OH) (5-CH3) 152 N=CHCsHa-
131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151
-0.97 0 .08"' 0.18 -1.51 0.46 -0.47 0.17
-5.96W 1.45u 1 .69 1.37 0.45 -0.29 0.49
0.17 0.21 0.24 -0.24 -0.15
-0.03 0.00 0.12 -0.61 -0.83
0.23 0.28 0.27 -0.11 0.10
-0.25 -0.26 -0.13 -0.51 -0.92
0.07 0.04 0.30 0.88 0.11 -0.10 -0.34 0.32 -0.12 0.16 -0.08 0.02 0.27
-0.15 -0.26 0.07 0.82 -0.10
0.14 0.14 0.38 0.89 0.18
-0.28 -0.39 -0.28
-0.51 0.39 -0.40 0.01 -0.55 -0.19 0.31
-0.28 0.28 -0.02 0.21 0.09 0.09 0.24
-0.07
-0.54 -0.06
0.09
154 155 156 157 158 159 160 161 162
N(C6Hj)z - ' 0OH 3,4-(OCFzO) OCF3 OCHF? OCONHz 3,4-(OCH,O) OCH,
164 165 166 167 168 169 170 171 172 173 174 175
OCFzCHFCl OCOCH, OCH2COOH OEt OPO(OCH3)z OCH(CH3)Z OC3H7 OCiHo OCjHii OCsHj OSOzCaH: 0-8-glucose
176 177 178 179 180 181 182 183 184 185
OCOC6Hj POCI, PCl, POF, PFZ PSClZ POZHPHz P(Cl)N(CHS), PO(CH3)t
- 3.87W -0.67
1.04 - 1.05 -0.05 -0.02 -0.88
-0.64 -0.87 0.38 1.05 2.08 0.93 -2.841.46
*MVlG *MV1 *MYUS *M2 *Nl&l *NSWl&&SWl *NUNN1&1 *MV2 *MV02 *MVM2 *MYUS&M 2 *K *MVY *MlV02 *M4 *NUNR *MR *MSWR *NUlR *MVR *NUNR BQ E l
43 43 2 2 14 14 4 6 46 2
24.25 25.82 -0.25 24.26 0 . 1 3 31.31 -0.38 30.04 -0.18 37 .88' -0.63 33.01D -0.27 34.64 0.08 37.45
92.5 58.1 74.1 44.1 44.1 172.2 72.1 72.1 88.1 87.1 103.2 59.1 86.1 102.1 72.15 105.1 92.1 156.2 104.1 120.1 135.2
48 43 43 43 43
48 43 43 43 43
0.10
-0.63
39.29D
134.2
*NUlR DO1
43
43
0.14
-0.19
41.03
150.2
*MVR DO1
43 43
-0.29 54.96 -0.49 2.85B -0.64 8.95B 0.04 0 .oo 7.86B 7.86B -0.14 11.28B 0 .oo 8.96B -0.51 7.87B 0 .oo 16.99 -0.06 17.30B - 0 . 0 7 12.47B 13.99B -0.44 12 .47B 22 .02B - 0 . 7 2 17 .06B - 0 . 4 5 17 ,06B -0.55 21 .66B -0.57 26.26B -0.35 27 .68B 0 .oo 36.70' 36.53D
168.2 16 . O 17 . O 82 . O 85 . O 57 . O 60 . O 46 . O 31 . O 95.1 133.5 59 . O 75 . O 45.1 125 . O 59.1 59.1 73.1 87.2 93.1 157.2 179 . O
*NR&R *O *Q *OXFFO*(C,D) *OXFFF *OYFF *ovz *010*(C,D) *01 *osw1 *OXFFY G F *ov1 *OlVQ *02 *OPO&O1&01 *OY *03 '04 *05 *OR *OSWR *0-BT6OTJ
49 44 2 9 45 51
121.1 117.9 101.9 85 . O 69 . O 133.9 80 . O 33 . O 110.5 77 .o
*PO&GG *PGG *PO&FF *PFF *PS&GG *PWQ *PHH *PGN1&1 *PO&1&1
0 .oo
19.77 14.93 23.40 14.98 15.55 31 .22' 20.88D 19.58 21.18 23.19 31.66
-0.26
0.00 -0.47 0.12 0.36 0.38 0.31
-0.22 -0.81 -0.37 0.36 0.35 0.18
0.07 -0.35 0.29 0.35 0.38 0.35
-0.16 0.12 0.39 0.35 0.39
-0.16 -0.27 0.36 0.28 0.31 -0.33 -0.24 0.04 -0.45 -0.25 -0.32 -0.34 -0.03 0.33
-0.17 0.26 0.39 0.37 0.41
0.13 0.43 0.61 0.89 0.61 0.39 0.26
0.23 0.93 0.49 0.77 0.12 0.84 0.17
-0.08 -0.42 0.16 0.18 0.50 -0.39 0.11
32 .33B 20.16D 21 .42D 9.58D 11.02D 28 .29D
0.56
0.30
0.28
12.19D 27.01D 19.93D
0.10
0.10 0.10 0.10 0.10 0.25 0.36
0.21 0.80
0.53 0.81 0.26 0.73 0.20 0.05 0.38 0.42
0.22 0.30 0.22 0.25 0.25 0.34 0.36
43 14 14 2 43 47 4
43 14 14 2 43 6
13 13
50 44
2 9 45 51
22 22 2 2 43 43 51 51 2 2 52 2 2 53 2 2 2 2 2 2 2 2 2 4 43 43
43 54 54 41 41 54 2 54 41 54
43 53 41 41 41 53 2 41
Nli.
Function,'
-,,
c
186 187 188 189 190 191 192 193 194
rT
0 42 0 O?
0 35
I97
(I
40
198 199 200 2 01 202 203 204 203 2 06 207 208 209 210 211 21 2 213 21 4 21 5 216 21 7 218 219 220 221
20 35
0 05%
0 0 0 0 0 0
1 23
0 61
195
0 70
-
--4 76iV 0 39 -1 8 2 1 65
-2 I 228 229 230 231 23% 233 234
38 11
29 80
0 02 0 05 0 25 0
46
0 63 0 79 0 40 0 41 0 33 0 54 0 75 0 52
0 ,ir5 1 44 0 41
- 1 58 -1 63
0 60 0 1
9
36 63 63 64 48 2 40 40 41 2
64 4
63
65
2
40 40 41 2
65 65 65 65
Function begins with attachment atom, sorted alphabetically on attachment atom and within each such grouping: first, if' no (1 o r 1 1 , then alphabetically on remainder; second, if no C, then on H and alphabetically on remainder; third, C then I i then allJhabetically on remainder. l2 A11 T values from partition coefficients measured in this laboratory using octanolwatci' solvent system and substituted benzene solutes unless footnoted t o give other sources or suffixed t o give other solute systcms: W --- from substituted biphenyl solutes; X = from substituted phenoxyacetic acid solutes; Y = calculated from 0 1 I deiiv:iLive: Z = from substituted toluene solutes. Calculated from u,,,and u,, given in this table according to the proc.t-durr (iutlined in the text. d Molar refraction using A. I. Vogel's [ J . Chem. Soc., 1833 (1948) ] atom, group, or structural Ru lyell(,w l i n d values unless suffixed: A = calculated [usually from index of refraction, density, and molecular weight from I'firentz 1,orentz formula (eq I ) ]using Vogel's (1948) values for corrections; B = atom, group, or structural H, ( = R c red line values from Ingold ("Structure and Mechanism in Organic Chemistry," 2nd ed, Cornel1 University Press, Ithaca, N. Y . , 1969. 1 1 1 ~142 1.52).Note: Table 10.1 "alcohol" and "ether" values inverted; C = approximate; D = bond values [including 1JlJnd t o ( ' 1Jf substrate) from A. I. Vogel, W.T. Cresswell, G. €3.Jeffery, and J. Leicester, J . Chem. soc., 514 (19.521,and cswrlier i.ct:'c.iences cit,ed therein (general); A. I. Vogel, W. T. Cresswell, and J. Leicester, J . Phys. Chem., 58, 174 (1954) (Sn, Si, ( i f , . and fIg bonds); A. A. Foxton, (2.H. Jeffery, and A. I. Vogel, J . Chem. SOC. A , 249 (1966) (P bonds); R. G. Gillis, Rev. l'unj A p p / . C'hcm., 10, 21 (1960) (bonds to C, H, 0, and self), updated by P. M. Christopher and T. L. Patterson, Aust. J . ( ' h ~ m . 21, . 2:173 f 19683, and earlier references cited therein; C. Stijlzer and A. Simon, Chem. Ber., 96, 1335 (1963) (P bonds to I,', C I . N ; 11. S a y r e , J . Amer. Chem. Soc., 80, 5438 (1958) (P bonds to S). From "Handbook of Chemistry and Physics," 531.~1 ed, Chemical Rubber Publishing Co., Cleveland, Ohio, 1972. The WLN follow as closely as possible the rules in "The '
~
Aromatic Substituent Constants
Journal ofMedicinal Chemistr?, 2973, Vol 16, N o 11 1213
Wiswesser Line-Formula Chemical Notation,” E. C. Smith, Ed., McGraw-Hill, New York, N . Y., 1968, with these additions. (1) T h e WLN begins a t the point of attachment: (a) if the substituent group becomes part of an aromatic fused ring system, the substituent is cited as a closed ring and the attachment locants (for the substituent ring) are marked with asterisks. T h e notation is followed by a parentheses showing attachment locants on the parent ring; (b) if the substituent completes a single saturated ring on an aromatic ring it is treated as a linear chain with a two-point attachment; (c) the WLN for a carbocyclic or heterocyclic ring as a substituent begins with a space and then a locant showing the attachment point on the substituent ring. (2) Methyl contractions are made on “X,” “Y,” and “K” symbols but not on rings. (3) Multipliers are used according to normal rules. (4) T h e # symbol denotes a saturated alkyl chain of undetermined length. (5) If a “?” begins the notation, the structure is not definable by WLN. The following refrences refer to u m and up, respectively: (1) 0. Exner, Collect. Czech. Chem. Commun., 31, 65 (1966); (2) D. H. McDaniel and H. C. Brown, J . Org. Chem., 23, 420 (1958); (3) W. A. Sheppard, Trans. N . Y . Acad. Sci., [11] 29, 700 (1967); (4) H. H. Jaff6, Chem. Rev., 53, 191 (1953); (5) M. Charton, J . Org. Chem., 30, 552 (1965); (6) M. Charton, ibid., 28, 3121 (1963); (7) P. Cecchi, Ric. Sci., 28, 2526 (1958); (8) P. Zuman, “Substituent Effects in Organic Polarography,” Plenum Press, New York, N. Y., 1967, p 76; (9) L. M. Yagupol’skii and L. N. Yagupol’skaya, Dokl. Chem., 134, 1207 (1960); (10) J. A. Landgrebe and R . H. Rynbrandt, J. Org. Chem., 31, 2585 (1966); (11) V. V. Orda, L. M. Yagupol’skii, V. F. Bystrov, and A. U. Stepanyants, J. Gen. Chem. U S S R , 35, 1631 (1965); (12) R . Stewart and L. G. Walker, Can. J. Chem., 35, 1561 (1957); (13) W. F. Little, C. N. Reilley, J. D. Johnson, K. N. Lynn, and A. P. Sanders, J. Amer. Chem. SOC.,86, 1376 (1964); (14) T. Nishiguchi and Y. Iwakura, J. Org. Chem., 35, 1591 (1970); (15) 0. Exner and J. Jon&, Collect. Czech. Chem. Commun., 27, 2296 (1962); (16) M. F. Hawthorne, T. E . Berry, and P. A. Wegner, J. Amer. Chem. SOC.,87, 4746 (1965); (17) L. I. Zakharkin, V. N. Kalinin, and I. P. Shepilov, Dokl. Chem., 174, 484 (1967); (18) V. F. Bystrov, L. M. Yagupol’skii, A. U. Stepanyants, and Yu. A. Fialkov, ibid., 153, 1019 (1963); (19) W. A. Sheppard, J. Amer. Chem. SOC.,87, 2410 (1965); (20) G. B. Ellam and C. D. Johnson, J . Org. Chem., 36, 2284 (1971); (21) M. Charton and H. Meislich, J. Amer. Chem. SOC.,80, 5940 (1958); (22) L. P. Hammett, “Physical Organic Chemistry,” McGraw-Hill, New York, N. Y., 1940, p 188; (23) J. Smejkal, J. Jona’B, and J. FarkaE;, Collect. Czech. Chem. Common., 29, 2950 (1964); (24) M. Charton, J. Chem. SOC.,1205 (1964); (25) J. H. Smith and F. M. Menger, J. Org. Chem., 34, 77 (1969); (26) F. Fringuelli, G. Marino, and A. Taticchi, J . Chem. SOC.B , 1595 (1970); (27) Yu. S. Shabarov, T. P. Surikova, and R . Ya. Levina, J. Org. Chem. U S S R , 4, 1131 (1968); (28) J. C. Kauer and W. A. Sheppard, J. Org. Chem., 32, 3580 (1967); (29) W. A. Sheppard, J.Amer. Chem. SOC.,92,5419 (1970); (30) V. F. Bystrov, Zh. N. Belaya, B. E. Gruz, G. P. Syrova, A. I. Tolmachev, L. M. Shulezhko, and L. M. Yagupol’skii, J. Gen. Chem. U S S R , 38, 963 (1968); (31) W. N. White, R . Schlitt, and D . Gwynn, J. Org. Chem., 26, 3613 (1961); (32) C. Weiss, W. Engewald, and H. Muller, Tetrahedron, 22, 825 (1966); (33) J. J. Ryan and A. A. Humffray, J. Chem. SOC.B , 842 (1966); (34) W. F. Little, C . N . Reilley, J. D. Johnson, andA. P. Sanders, J.Amer. Chem. SOC.,86, 1382 (1964); (35) J. K. Kochi and G. S. Hammond, ibid., 75, 3452 (1953); (36) L. M. Litvinenko, Bull. Acad. Sci. U S S R , Diu. Chem. Sci.,10, 1653 (1962); (37) A. N. Nesmeyanov, E . G. Perevalova, S. P. Gubin, K. I. Grandberg, and A. G. Kozlovsky, Tetrahedron Lett., 22, 2381 (1966); (38) H. Alper, E. C. H. Keung, and R . A. Partis, J . Org. Chem., 36, 1352 (1971); (39) P. Zuman, “Substituent Effects in Organic Polarography,” Plenum Press, New York, N. Y., 1967, p 325; (40) N. V. Kondratenko, G. P. Syrova, V. I. Popov, Yu. N. Sheinker, and L. M. Yagupol’skii, J . Gen. Chem. U S S R , 41, 2075 (1971); (41) M. G. Hogben and W. A. G. Graham, J. Amer. Chem. SOC.,91, 283 (1969); (42) E. S. Lewis and M. D. Johnson, ibid., 81, 2070 (1959); (43) 0. Exner and J. Lakom9, Collect. Czech. Chem. Commun., 35, 1371 (1970); (44) J. Hine, J . Amer. Chem. SOC.,82,4877 (1960); (45) F. S. Fawcett and W. A. Sheppard, ibid., 87,4341 (1965); (46) J. C. Howard and J. P. Lewis, J. Org. Chem., 31, 2005 (1966); (47) E. P. Serjeant, Aust. J. Chem., 22, 1189 (1969); (48) M. Charton, J. Org. Chem., 30, 557 (1965); (49) E. N. Tsvetkov, D. I. Lobanov, and M. I. Kabachnik, Chem. Abstr., 66, 28299r (1967); (50) E . N. Tsvetkov, D. I. Lobanov, and M. I. Kabachnik, ibid., 64, 12523f (1966); (51) R . Van Poucke, R . Pollet, and A. De Cat, Bull. SOC.Chim. Belg., 75, 573 (1966); (52) P. J. Bray and R . G. Barnes, J. Chem. Phys., 27, 551 (1957); (53) H. L. Retcofsky and C. E. Griffin, Tetruhedron Lett., 18, 1975 (1966); (54) H. Schindlbauer and W. Prikoszovich, Chem. Ber., 102, 2914 (1969); (55) E. N. Tsvetkov, D. I. Lobanov, L. A. Izosenkova, and M . I. Kabachnik, J . Gen. Chem. U S S R , 39, 2126 (1969); (56) L. D. Freedman and H. H. Jaff6, J. Amer. Chem. SOC.,77, 920 (1955); (57) E. N. Tsvetkov, D. I. Lobanov, M. M. Makhamatkhanov, and M. I. Kabachnik, Tetrahedron, 25, 5623 (1969); (58) K. Kalfus, M. VeEefa, and 0. Exner, Collect. Czech. Chem. Commun., 35, 1195 (1970); (59) W. A. Sheppard, J. Amer. Chem. SOC.,84, 3072 (1962); (60) B. J. Lindberg, Acta Chem. Scand., 24, 2852 (1970); (61) W. A. Sheppard, J. Amer. Chem. SOC.,85, 1314 (1963); (62) L. N. Sedova, L. Z. Gandel’sman, L. A. Alekseeva, and L. M. Yagupol’skii, J. Gen. Chem. U S S R , 39, 2011 (1969); (63) A. Kucsman, F. Ruff, S. Sblyom, and T. Szirtes, Acta Chim. Acad. Sci. Hung., 57, 205 (1968); (64) V. G. Boloshckuk, L. M. Yagupol’skii, G. P. Syrova, and V. F. Bystrov, J. Gen. Chem. USSR, 3, 105 (1967); (65) Z. PlzLk, F. Mare:, J. Hetflejk, J. Schraml, Z. PapouE;kov&,V. Baiant, E. G. Rochow, and V. Chvalovskj., Collect. Czech. Chem. Commun., 36, 3115 (1971). From M . M. Otto, J. Amer. Chem. SOC., 57, 1476 (1935). SOz from S O Z ( O R )=~ 7.838; SO from SO(OR)* = 8.046; Vogel’s values (1948).d From C. E. Lough, Suffield, Memorandum No. 17/71. Aromatic oxygen from -OH = 1.76. pH = 6.0; phosphate buffer. T. Fujita, private communication. From G. H. Jeffery, R. Parker, and A. I. Vogel, J. Chem. SOC.,570 (1961), average for thenoates and thienyl ketones. From H. H. Huang and S. C. Ng, J. Chem. SOC.B , 582 (1968), report 41.8 for naphthalene. p Vogel’s group value (1948).dBond value is 26.387 - 1.676 = 24.711 where 26.387 is from Vogel’s (1948) 25.359 phenyl value plus his 1.028 hydrogen value. Ingold’s value 25.93 - 1.092 = 24.838. * From T. P. Vishnyakova, Y. M. Paushkin, and T. A. Sokolinskata, J. Gen. Chem. USSR, 33, 3615 (1963), from monosubstituted isooctyl and cyclohexyl derivatives. Disubstituted showed -0.90 “exaltation.” From S. Landa and V. Machacek, Collect. Czech. Chem. Commun., 5, 1 (1933). From Vogel, et al. (1952),dwhich gives a factor of 2.3 for conversion of single to double bonds. Christopher and Patterson (1968)destimate (1-0) bond as 10.63, thus we obtain 24.449 for (I=O). Gillis (1960)dgives (C-I) as 14.61. t Vogel, et al. (1952),dgive PhNO? = 32.72 in Table 53. Thus 32.72 - 25.36 = 7.36. This procedure was not used for other values because of better agreement with standard method. From E. Lieber, C. N. R. Rao, T. S. Chao, and W. H. Wohl, J . Sci. Ind. Res., Sect. B , 16, 95 (1957), for Ph derivative. PhNHSO?NHS0zNH2was the gift of Dr. R . Appel, University of Bonn, Germany. 1 ~ .Using C,,-NR? = 3.22 or Car-NHR = 2.96 bond values from Vogel, et al. (1952).dOther values of Car-X were not used since these agreed closely with normal values. Approximate: group value for N3 plus bond value for tetrazolyl. From Y. Ichikawa, T. Yamano, and H. Fujishima, Biochim. Biophys. Acta, 171, 32 (1969). From 0. E. Schultz, C. Jung, and K. E. Moller, 2.Naturforsch., B , 25, 1024 (1970). From R . Poretz and I. Goldstein, Arch. Biochem. Biophys., 125, 1034 (1968). bb Bond: 24.711 - H F = 24.475 for CsHd-3-F. cc From W. A. Sheppard, J. Amer. Chem. SOC.,84, 3064, 3072 (1962). Calculated from data on PhSF:. d d From V. Lee, M.S. Thesis, San Jose State College, Aug 1967. J
+
( < l %between ) the Rc (red line) values reported by Ingold and the RD(yellow line) values of Vogel. Very few atom or group refractivities have been reported for organometallic substituents, and so the more common bond values were used. Our MR values always
include the bond to the carbon atom of the parent benzene ring. We have not calculated the refractivity for charged substituents as no suitable values are available (except the octet values given by Ingold, which have not been widely used).
N i
N=191
k0.222
-11.52
-0.ZU
S.0.25
R=-O.O9 l0.051*0.21 [0.131
w 3
I
'ii
4, -1
~
-N,
ot
'-11.00
0.ou
0.32
0.60
0.88
1.16
: I.VV
---e----+ 1 71 2. a3
3
Figure 2. Plot of 5 us.
for 191 substituents.
The following examples illustrate these methods. (1) -NHCSNHz (by Vogel's group values)
NH cs secondary aromatic amine xanthates 4.678 + 13.07 + NHZ p r i m a r y aliphatic amine = 22.19 4.438 ( 2 ) -0COCsHs (by Ingold's group values with exaltation)
-0aromatic PhOR 2.18
=o
-C-
PhC(OR)=O + 2.413 + 2.90 + CcH; footnote p , Table I = 32.33 24.84 We have used the symbol MR for molar refractivity in"
"
stead of Rhf or PE in order to avoid confusion with the chromatographic RM = log [ ( l / R t ) - 11 and to avoid confusion between electronic polarization ( P E )and polarizability ( a )since PE = MR = y3xNoc.lOa.= 4. Structural Notation. In planning for computerized multiple parameter regression analysis with potentially thousands of sets of data and hundreds of different substituents and parameters, it is highly expedient (and much more accurate) to machine load various parameters. This further facilitates large-scale comparisons of parameter types. Machine loading requires the storage and retrieval of values classified both as to substituent and parameter type. Substituents require a suitable system for the handling of chemical structures and substructures.
For these reasons Wiswesser line notation has been given for the functions in Table I. A number of such systems have been thoroughly investigated,l* and it is evident that the Wiswesser line notation (WL?j)l4d combines three important attributes: low-cost file construction and searching, readability, by the chemist (cf. connectivity tables), and the widest acceptance thus far by both industry and the literature searching services. We have modified the canonical WLN rules14d to a very slight extent to better specify the structure of a molecular fragment (Le., substituent) rather than the whole molecule. A simple subroutine will suffice to make them compatible with a file encoded in canonical WLX. These modifications are explained in Table I. This system will. furthermore, interface with our extensive structure-activity and physical parameter data bases.+t Discussion
There are two general aspects of the lipophilic constant which must be kept in mind when comparing T from different solute systems. The value of x for a given function is, for the most part, determined by the intrinsic lipophilic or hydrophilic character of the substituent. However, this intrinsic value can be influenced by the environment which includes both substrate and solvent; that is, T is defined operationally. The electronic effect on 7i can be easily appreciated by noting that log P-OH/benzene$ is -0.67, while the corresponding value from aliphatic alcohols is -1.16. The strong influence of electron withdrawal on the T values of alkyl groups has been shown t o be quite general.15 This effect can be seen when a methylene group is placed between two electron-withdrawing functions: T - C Y = -0.57 and T-CHzCN = -0.57; a-COCH3 =
Journal o f M e d i c i n a l Chemistry. 1973, Vol. 16, No. 11 1215
Aromatic Substituent Constants
Table 11. Octanol-Water
K
Constants from the Benzene System and Hammett
No.
Substituents“
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
3-C1, 4-C1 3-C1, 4-OH 3-C1, 4-CH3 3-C1, 4-OCH3 3-C1, 4-NH2 3-Br, 4-Br 3-Br, 4-CH3 3-Br, 4-OCH3 3-Br, 4-OH 3-Br, 4-NH2 3-1, 4-OH 3-F, 4-OH 3-CH3, 4-CH3 3-CH3, 4-OCHs 3-CH3, 4-NO2 3-CH3, 4-N(CH3)2 3-CH3, 4-C1 3-CH3, 4-NHz 3-CH3, 4-OH 3-OCH3, 4-OCH3 3-OCH3, 4-C1 3-OCH3, 4-OH 3-NO2, 4-NO? 3-NO2, 4-C1 3-N02,4-Br 3-NO2, 4-OCH3 3-NO2, 4-CH3 3-NO2, 4-NH2 3-NO2, 4-OH 3-OH, 4-OH 3-NH2, 4-NH2 3-NH2, 4-OH 3-NH2, 4-CHa ~-N(CHJ)P, 4-CH3
17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Obsd
Calcdb
1.25d 0.02 1.2gd
1.42 0.52 0 . 0 4 -0.05 1.27 0.23 0.69 0.27 -0.52 1.72 0.15 1.42 0.09 0.84 0.19 -0.37 0.45 -0.53 1.12 - 0 . 3 0 0.54 -0.26 0.28 0.69 0.74 -0.30
-0.23 1.51 0.22 0 . 16e 0.52 -0.42 0.99 0 . 17d 0.681
1.27 -0.67
1.29 -0.81d -0.18 0.08
u
Constants for Multiple Substituents
ZU
27r
Obsdc
0.17 -0.72
-0.11
-0.04
0.69 -0.69 -0.56 -0.55d 0.43 O . l l d 0.58 -0.30 0.28 0.17d -1.51 -0.30 -0.95 -0.34 -1.34 - 1.25 - 1.98d -2.46 -1.90 -1.51 -0.67 -0.731 0.74 0.681
-0.12 0.34 -0.33 1.38 0.90 0.83 0.41 0.50 -0.28 -0.21 -0.18
~-
Calcd* 0.60 0 .oo 0.20 0.10
-0.29 0.62 0.22 0.12 0.02 -0.27 -0.02 -0.03 -0.24 -0.34 0.71 -0.90 0.16 -0.73 -0.44 -0.15 0.35 -0.25 1.49 0.94 0.94 0.44 0.54 0.04 0.34 -0.25 -0.82 -0.53 -0.33 -0.32
No. 35 36 37 38 39 40 41 42 43 44 45
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
66
Substituents“ 3-NO2, 5-NO2 3-NOz, 5-C1 3-NOz, 5-OH 3-NO2, 5-NH2 3-NO2, 5-OCH3 3-F, 5-OH 3-F, 5-NH2 3-C1, 5-C1 3-C1, 5-OH 3-C1, 5-NHz 3-Br, 5-Br 3-Br, 5-OH 3-Br, 5-N02 3-1, 5-OH 3-CH3, 5-CH3 3-CH3, 5-C1 3-CH3, 5-NOs 3-CH3, 5-OH 3-CH3, 5-NH2 3-OCH3, 5-OCH3 3-OCH3, 5-C1 3-OCH3, 5-OH 3-OH, 5-OH 3-OH, 5-NH2 3,4,5-(OCH3)3 1,3,5-(CHs)3 1,3,5-(OH)3 1,3,5-(N02)3 1,3-(OH)?, 2-NO2 2,4- ( N O P ) ~ , I-CH:, 3-OCH3, 4-OH, 5-NO2 3-OH, 4-OCH3, 5-NOZ
%
ET
Obsd -0.64 0.33 -0.13 -0.76 0.03 -0.20 -0.83 1.25d 0.37 -0.25 1.62 0.50 0.51 0.80 1.07d 1.15d 0.32 -0.17 -0.73 0.08
Calcdb Obsdc Calcdb -0.56 1.39 1.42 0.43 1.08 1.07 -0.95 0.83 -1.51 0.55 -0.30 0.83 -0.53 0.46 -1.09 0.18 0.75 0.75 1.42 0.49 0.04 -0.52 0.21 0.72 0.78 1.72 0.19 0.51 0.58 1.10 0.47 0.45 1.12 -0.17 -0.14 0.35 0.30 1.27 0.28 0.64 -0.11 0.05 -0.67 -0.23 -0.04 0.05 0.24
-0.55 -1.33 -1.96 -0.60 1.29 -1.97 -0.95 -0.57
0.69 -0.69 -1.34 -1.90 -0.06 1.68 -2.01 -0.84 -1.62
-0.15
0.44
0.07
0.49 0.24 0.24 -0.04 -0.03
-0.97
0.43
0.46
-0.97
0.63
0.56
0.16
0 .oo
~
For K constants 3,4 represents the ortho derivative and 3,5 the meta derivative. The calculated value is simply the sum of the values from Table I for the monosubstituted benzenes ( T ) or benzene derivatives ( u ) . c From H. H. Jaff6, Table I, footnote g, ref 4. d See footnote **. e From Y. Ichikawa, T. Yamano, and H. Fujishima, Biochim. Biophys. A c t a , 171, 32 (1969). From 0. E. Schultz, C. Jung, and K. E. Moller, 2. Nuturforsch., B , 25, 1024 (1970). a
-0.55 and H - C H ~ C O C H=~ -0.69. A methylene unit normally increases H by 0.50 ~ n i t s . ~ Inbthe above two examples and many others of this type,l5 no increase in K is observed. Generally, however, there is no correlation of Ir-/benzene with electronic effects; for 93 substituents, T is completely uncorrelated with 3 and/or 6i ( r 0.21, s 1.5). Furthermore, there is no correlation of H with MR ( n = 116, r = 0.159, s = 1.30). The phenyl group is not quite additive (differing by about -0.2) when attached to another aromatic ring. In Table I, x-C& is 1.96, while H - C ~ H from ~ 2-phenylquinoline is 1.87, from 4-phenylpyridine it is 1.80, and from 2-phenylthiophene it is 1.93. The mean deviation from 2.13 is *0.24. Whether this is due to a steric or electronic effect (or both) is not yet clear. There is a range in H in Table I of -5.96-3.30 (over nine powers of ten). Many other functions, more lipophilic than those listed, can be constructed with confidence simply by adding CH2, halogen, or phenyl groups to a known function and following additivity rules in calculating ~ . ~ b It v ~ is 5relatively easy to obtain variation in H of 10-12 log units; that is, one can design molecules having only one functional group but varying as much as 100 billion in their relative hydrophobicity. Exner16 has commented upon the dominance of MW in giving apparent additivity in MR. This will undoubtedly be true of individual substituents; however, we find that for 220 substituents the correlation of MR with MW is not
-
-
high ( r = 0.759, s = 8.97). Thus, less than 60% of the overall variation in MR is accounted for by MW, and “volume” (approximated by MR) is only roughly correlated by “mass.” In other words, the density of the substituents is not very constant. This is interesting because (MW)1’3 is sometimes used as a n approximation to molecular radius in diffusion studies.17 Figure 1 shows a plot of up us. cm for 191 substituents. E x n e P and Taft, et a1.,19 have studied subsets of this group, but Figure 1 is an impressive demonstration of the general interdependence of these two substituent parameters, especially considering the variety of sources from which the data were obtained. (The single outlier corresponds to CH=CHCOOH. Since this substituent contains no special structural features compared to others, it is most likely that either or both of the parameter values are in error; they come from two different sources. No other values were found in the literature for confirmation.) Note that the full range of charged, uncharged, and even organometallic substituents is accommodated with surprising precision ( r = 0.903, s = 0.17). Considered as vectors, cm and cp are separated by an angle of only 25” (arcosine 0.903).8b On the other hand, the simple factorization of Swain and Lupton achieves a remarkably high separation of effects as shown in Figure 2. The correlation of r = 0.222 corresponds to a n angle of 77” (arcosine 0.222). Similarly, the angle between up and 3 is 39” ( r = 0.780), and the angle between a m a n d 3 is 13” ( r = 0.973).
Han5ch e t Since 5 and CR were calculated directly from um and u , ] , they are coplanar with them; that is, the angle between any other vector Z and the plane of 5 and CR or n, and ul, (or any two of the four) is the same; that is, the correlation coefficients will be the same. Thus it is clear that a n increasing angle (decreasing correlation coefficients) between the vectors will be reflected in plots such as Figures 1 and 2 by increasing scatter. Plotting a parameter against a simple multiple of itself will yield a perfect straight line. As the second parameter becomes more and more unlike the first, the points on the original line will disperse. eventually forming a perfect scatter plot. Hence, limited relationships found by Exnerl8 and Taft, et U L . , ’ ~ are. in this sense? artifactitious. This is confirmed by employing truly orthogonal vectors.8“ in which many of the special linear relations are eliminated. Subgroups on the basis of uniting atoms generally tend to have constant resonance values and differ only in field-inductive effects. On this scale,8* ( T , has about 30% resonance and 0,)50% resonance. not a very large difference. These results further confirm the dual nature of electronic substituent effec.ts.6.8,: Further discussion of the interrelations of parameters will be given in the accompanying paper on clustering.I7 Table I1 provides some insight into the additivity of ii and 0. For disubstitution and three examples of trisubstitution (consult JaffC’s survey, Table I, footnote g, ref 4), (T shows consistently good additivity. There are only four examples (16, 34, 54, and 65) where the difference between observed and calculated values is much greater than experimental error. In the case of ii,additivity is not nearly so good. The most pronounced effects occur when strong electron-withdrawing groups are placed on the ring with groups having lone pair electrons (-OH, - NHz). The -NO2 function or even halogen functions, when combined with -OH and -NH2. give higher than expected ~i values. Acknowledgment. We wish to thank Dr. Rolf Appel of the University of Bonn for a generous sample of PhNHSO2NHS02NH2 and Dr. W. A . Sheppard of the Du Pont Company for a sample of 3-NHzPhSFs from which we made PhSFj. References ( 1 ) N. B . Chapman and J . Shorter, E d . , “Advances in Linear Free Energy Relationships.” Plenum Press. New York. N.
Y..1972
UL
(2) ( a ) C. Hansch, J . Schaeffer, a n d R. Kerley, J . Bioi. C‘hem.. 247, 4703 (1972); (b) J . Fastrez and A. R. Fersht. B i o c h e n istr?. 12, 1067 (1973); ( c ) hi. Stockdale and M. .J. Selwyn. Eur. J . Biochem.. 21,565 (1971).
(31 ( a ) C . Hansch in “Drug Design.” Vol. 1. E . .I , Ariens. Ed.. Academic Press. Xew York, N. Y..1971, p 271; t b ) LV. 1’. Purcell, J . A . Singer, K . Sundaram, and G . L. Parks in “Medicinal Chemistry.” A. Burger. Ed.. Wiley-Interscience. S e w York. N.T..1970. p 164; ( c ) B . Duperray, (‘him. Thtv- , 6, 305 (1971); i d ) Adt’an. C‘hem. S u . No. 114 (1972); ( e ) R. b:. T a f t in “Steric Effects in Organic Chemistry.” M .S. S e w m a n , Ed.. LViley, New York, N.Y.. 1956. p 556. ( 4 ) ( a ) L. P. Hammett. ”Physical Organic Chemistry.” 2nd ed. McGraw-Hill. New York, X. T..1970; ( b ) ,J, E . Leffler and E . Grunwald. “Rates and Equilibria of Organic Reactions.” M’iley, New Cork. N.Y..1963. ( 5 ) i a i T . Fujita. .J. Iwasa. and C. Hansch. J . Amer. Chem. SOCC. 86, 5175 11964); ( b ) A, Leo, C. Hansch. and D. Elkins. Chem. R e v . , 71,525 (1971). (6) C . G . Swain and E . C . Lupton. J . Amer. C’hem. Soc.. 90, 4328 (1968)
( 7 1 K. R‘. Tat‘t and I. C . Lewis, J . Amer. Chem. Soc.. 80, 2436 (1958). (8) ca)S. H. Linger. Ph.D. Thesis, Massachusetts Institute of Technology, Cambridge. Mass.. Sept 15, 1970; ( b i S. H . Lnger and C. Hansch, J. M e d . Chem., 16,745 (19731. ( 9 ) A. Bondi. ./.f h ~ a Chem., . 68,441 (1964). 110) ( a ) D. Agin, I,. Hersh, and D. Holtzman, Proc. !Vat. r l c a d . Sci. [ - . S.. 53, 952 (1965); ( b ) C. Hansch a n d E . Coats. J. Pharm. Sci.. 59, 731 (1970). (111 B. R. Baker. “Design of Active-Site-Directed Irreversible Enzyme Inhibitors,” Wiley. New York, N . Y., 1967. (12) C. Hansch. S. L‘nger, and A. B . Forsythe, ./. MPd. (’hem.. 16, 1217 (1973). (131 F. it’. Baker, R . C. Parish. and L. M. Stock. J . Amer (’hem. Soc., 89, 5678 (19671. 114) ( a ) 31. F. Lynch, cJ, M . Harrison, LV. G . Towne? and J . E. Ash. “Computer Handling of Chemical Structure Informa-
tion.” MacdonaldiAmerican Elsevier, New York, N. Y.. 1971; ( b ) L. H. Campey. E. Hyde, and A. R. H. Jackson. (’hem. Brit.. 6, 427 (1970); ( c ) G. W. Gibson and C. E. Granito, . 4 m w Laborator?, 1, 27 (1972); i d ) E. G . Smith. “The LVisxesser Line-Formula Chemical Kotation,” McGraw-Hill, New York, N . Y., 1968. (15) C. Hansch. A . Leo. and D . Nikaitani. J . Org. C‘hem., 37, 3090 11972). (16) 0 .Exner, C‘ollect. Czech. Chem. Commun., 31,3222 (1966). ( 1 7 ) S . Kitahara, E. Heinz, and C. Stahlmann, .Vatwe (London). 208,187 (19651. (18) 0. Exner and ?J. LakomC.. C o i l e ct. C z e c h . C.’hem. (’ommun.. 35, 1371 i 1970). and earlier references cited therein. (19) R. W. T a f t . E . Price, I. R. Fox, I. C. Lewis, K . K . Anderson, and G . T. Davis. J Amer. Chem. S o c . , 85,3146 (1963).
