FINAL REPORT
on
EVALUATION OF A COMPUTER METHOD TO PREDICT
OCTANOL WATER PARTITION COEFFICIENTS
TECHNICAL DIRECTIVE 12
by
Albert J. Leo
SUPPLEMENT 3.
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The Octanol/Water Partition Coefficient of Aromatic Solutes:
The Effect of Electronic Interactions, Alkyl Chains,
Hydrogen Bonds and Ortho Substitution
By A. Leo, Department of Chemistry, Pomona College,
Clarenont, California 91711, U.S.A.
Summary
The calculation from structure of the hydrophobia parameter, log P
(octanol/water), involves the addition of fragment values (or of IT
constants to parent log P) plus correction factors for interactions not
present in the standard state from which the f or u values were determined.
In this paper the important correction factors for multply-substituted
aromatic solutes are classified as: electronic, negative ortho. hydrogen
bonding, and alkyl-aryl. The electronic factor F is best treated as a
continuous function in a manner similar to Haminett's pa product. Both
field and resonance components appear to be present in the electronic
effect. Sigma and p values for 50 substituents are reported in a
generalized structural form which makes possible estimation of many others.
While the other factors - FO , f^g , and F - are probably continuous
functions also, they are conveniently treated as "quantized". Calculated
in this way, the standard deviation for nearly 400 solutes amounts to less
than twice the estimated error in their measurement, and thus a more
precise estimation of these effects is unwarranted at this time. The
overall equation is: observed log P = additive log P + pa - 0.28F +
o
- °-17v
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Introduction
The measurement of the distribution of various solutes between two
immiscible liquids has a long history in physical and biological
chemistry beginning with Hernst1 who defined the constant K =
*Corg^(Cpolar*' The polar liwi* was most often water, and the
expression held as long as the solute concentration measured in each phase
was that of the same species. The theory, and methods for calculation of
this parameter from structure, have been the subject matter for a review
articleZ and several .books. 3"5 Applications of the hydrophobic parameter
are being reported at such a rapid rate that a bibliography is nearly
outdated by the time it reaches print, but the following references will
serve to lead the reader to some of the primary areas: drug and pesticide
design,6*'*' pharmacokinetics,6c anaesthesiology,6d environmental transport
and soil binding,^,/ toxicology,^ bioaccumulation,** protein folding,**
enzyme binding,*?-* enzymic reactions in non-aqueous solvents^ and
host-guest complexation.6^ There exist, in both government and industry,
files of organic structures numbering in the hundreds of thousands for
which hydrophobic parameters are desired. Measurement is out of the
question for the majority of them. Calculation by computer is the only
feasible, way of meeting the need in a reasonable time frame.
In the present paper, octanol/water partition coefficients, in the free
energy-based form of log P.7 are analyzed in order to quantify the effect
of substituent types and their position on an aromatic ring. The purpose
of the analysis is twofold: first, to more accurately predict log P
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values from structure, and second, to better understand the nature of the
solvation-desolvation forces as a small solute passes from an aqueous phase
to a lipid-like phase. As a basis for solvation theory, this analysis can
only be suggestive, because the basic forces which determine
"hydrophobicity" (that is, the preference for a lipid phase over water) are
still the subject of an intense debate.8
Hansch and his coworkers were the first to appreciate how the linear
free energy approach of Hanonett9 could be applied to partitioning
phenomena. In the first successful effort to place log P (octanol/water
assumed hereafter, unless otherwise specified) on an additive-constitutive
basis, Fujita, Iwasa, and Hansch1 °discussed the electronic effect in
disubstituted benzenes in terms of the change in the sum of * constants
compared to the sum of the individual IT constants from monosubstituted
benzene, the standard state for TT; that is,
nx(std.) = los pc,H|rx - los PC A
65 66
Vaniline solute syst.) = loS UCX " Io8 PCH.NH
MX = Vaniline) " nx(std.)
These authors related All to the Hammett -.a constant9 by the expression
AIIX = £ffX * C
For meta and para derivatives in the aniline solute system,
f = 0.90 and c = 0.016.
The respective values for the phenol solute system are 0.82 and 0.61
derivatives were not treated.
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Instead of developing a set of AH values for the aniline analogs,
another for phenols, a third for phenoxyacetic acids, etc., a wore
generalized approach is to consider one of the substituents, X, acting on
the other, Y, in a way which changes the sum of their II values. Equation
(2) expresses this if we consider Y = -NHj and X is any substituent with
strong electron-withdrawing power, such as -NC^, -CN, etc. The latter
groups will hereafter be referred to as "Inducers" (I) which act upon
"Responders"
o 4 bo
The first three terms on the right-hand side can be considered as the
"simple additive" log P (ALP) and the last term the interactive factor(s)
which for electronic effects is designated F .
In the early, paper defining the constant, Fujita et al.10theorized
that An was a positive value, at least when Y = -OH or -NH2, because in
the octanol/water solvent system the superior hydrogen bond-accepting
properties of octanol were favored when an electron-attracting second
substituent increased the acidity of the -OH or -NH group. Since that
early work, Fujita has expanded this concept n 12 to consider the
interaction to be bidirectional; that is, each substituent can be
assigned both a a value as an Inducer and a p value as a Responder. It
is not difficult to imagine how a substituent, such as -CONH. (o = 0.36),
can act as an Inducer when it is on a ring with -NH . On the other hand,
-------
if it is present with -N(>2
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The data available to early investigators of this field appeared to
support the view that the hydrophobicity of alkane substituents is
essentially unaffected by the character of the aromatic ring to which they
are attached. A practical calculation scheme can be based on this
assumption, for in a data set of modest size only toluene appears
anomalous. The data presented in this paper will support the view that
the methyl group in toluene can be treated the same as any methyl group
in an aliphatic or alicyclic compound, but if the aromatic ring to which
it is attached has any other substituent, its hydrophobicity is slightly
lower. This is in agreement with an earlier paper15 which called
attention to the fact that the relationship between log P and molecular
volume was different for aliphatic hydrocarbons than for aromatic.
METHODS
In order to perform a proper multi-variate analysis of data cast in
the form of Eq. (5), considering that F . F , F..-, and F . will each
u o atf a
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determined in this paper is not possible. Another source of variance
arises from the failure of most investigators to maintain a constant
temperature of measurement or to report it in any event. Even though for
the aromatic solutes in this study, the temperature coefficient ( log
P/degree) is of the order of only 0.002, this could be significant in
evaluating the smaller effects such as F .
a*
When more than one log P value was reported for a given solute, the
choice for inclusion in Table 5 was made after considering the following:
a) limits of error, if given; b) need to suppress ionization; c) probable
precision of analytical method; d) agreement with a third determination.
It should be noted that sometimes a choice was not warranted and an average
value was taken. FO and FQ^, can each operate in a solute independently
of the others, and so appropriate subsets of Table 5 were selected to
analyze these effects first. VQ and Ffffl are most often superimposed on F
or Fa$» and were analyzed later.
Since one of the objectives of this study was to improve the
computerized calculation of the hydrophobic parameter, log P,18 it was of
high priority to keep Fff, as simple as possible. It was apparent that a
procedure based on Fujita's method11 of separately accounting for om and
a as well as allowing each substituent to act bi-directionally would
result in calculations having a high precision. Offsetting this would be
some formidable programming problems plus the necessity of determining a
great number of p values for each substituent acting as a responder. The
three important simplifications developed in in this paper are: 1) use of
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a single O constant (slightly different from Hammetfs) for oz, nr:, and j^
interactions; 2) limiting bi-directionality (I/R) to about one-third
the total substituents; 3) use of "generalized" substituent structures
wherever possible to greatly reduce the number of p and o values needed
for calculation.
At first it appeared possible to treat Fff as if it occurred at discrete
levels. The highest level would apply where the X of the solute in Eq.
(5) was of the strongly electron-attracting type: -N02, -CN, or -N=
(i.e., pyridine, following the Jaffe convention of treating the fused
nitrogen as a substituent) characterized by a large a and low P, while Y
was of the electron releasing type: -0-, -NH2. Using Eq. (5) and
regression analysis with/AIt^ represented by an indicator variable taking
the value of 2, 1. or 0, an equation was obtained for 250 solutes which
reduced the standard deviation approximately threefold. Treated in this
"quantum level1!, fashion, FO could be either +0.29 or 2(+0.29) with no
distinction made between o^m^, and JQ^. interactions. This procedure
presented no serious problem in designing a computer algorithm, and
interestingly enough, seemed to show the effect to be a multiple of
Rekker's "Magic Constant".5 Some serious limitations of this "quantized"
approach appeared when a wider selection of data was studied, and it became
apparent that fg could be more effectively treated as a continuous
variable, i.e. as the product po. To obtain values appropriate to their
hydrophobic effect, the partitioning data were used and a simple
program for successive approximations19 was applied to Eq. (5) rewritten
as:
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OLP = ALP + p 0
1 A
where OLP = observed log P of X-C-1L-Y;
ALP additive log P = log P_ _ -+IT + IT __
C6H6 X Y
PY°X
Ninety-two solutes from Table 5, which included only those whose
exclusive role as I or R was evident, served as the determinant set. Since
an earlier relationship based on the Eammett constant had already been
established, the average of am and o was entered as the first
approximation on which the first level p values would be estimated. The
successive approximations proceeded until the change was less than 0.01
in either parameter. As input, both sigma inductive, OT ,16and the field
effect,-? ,15 were also tried, but the final set of a/p values were
essentially identical. They appear in Table 1 together with specific
examples of the generalized structures of substituents for which the
calculations can be applied. Using the "training-set" results in a
regression analysis of a larger subset of Table 5, it was determined that
the simplifications discussed above were statistically justified, and in
addition, it was possible to treat the halogens as a single class.
The partition coefficient appears to follow other physical chemical
parameters in respect to the difficulty of separating and evaluating polar
and steric effects for ortho substituents.20 21 Ogino et al.22 developed
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10
an equation using op, Es, and.? to explain the AH observed in 2- and/or
6- substituted guanamines where bulky groups keep the two rings fro,,, being
planar. To account for the electronic effect, Op was used (because of the
lack of reliable aQ values) and-? added as a correction term.
It is reasonable to suppose that, like ring twisting, substituent
twisting could lead to the lowering of log P. an effect frequently seen in
ortho substitution. However, since Es values were not available for nany
of the substituents studied, and a calculated Es23 did not significantly
reduce the variance over a simple "quantized" correction, the latter,
simpler procedure was pursued. For all 1,2-disubstituted solutes, where
intramol H-bonding would not affect log P (see below), the difference of
108 *ortho ~ ave"8e log PmetaSpam was tabulated. Where a value for only
the meta or j>ara isomer was available, it was used in place of the average.
In the cases where the difference (a negative number) was significantly
different from zero (i.e., lower than -0.1), both members of the pair were
entered into the fo Table 3. With two exceptions it was possible to use
the same generalized substituent structures used in Table 1 for F . The
o"
average for all the low-level differences (e.g. where Y = -0- or -OH)
was -0.28. This substituent class was taken as the lowest level for F
o*
and as an indicator variable in the regression equation, each menber was
given a Rvalue of 1. On this scale the highest factor assigned (for
1,2-benzenedicarboxamide) was 5.* Other FO values were assigned the
nearest multiple of the difference, ortho - average of (meta/para), for the
*For example: Log P of 1,2-benzenedicarboxamide = -1.73; for
the 1,3-analog, log P = -0.21; Alog P = -1.52; -1.52/0.28 = 5.
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11
substituents qualifying for any given generalized structure.
The inner square in Table 3 indicates the interaction of
1,2-substituents where intramol H-bonding greatly increases log P. These
are given an indicator variable value of 1.0 in appropriate regression
equations. This includes the tff described above, and thus both indicator
variables are never called for with a 1,2-disubstituted aromatic compound.
With one possible exception, fQ does not appear to be a continuous
variable, in the compounds studied, nor was more than one level needed to
account for it.
RESULTS AND DISCUSSION
Electronic Effect
The first subset of Table 5 selected for analysis (£l-£l96) are those
solutes which should only show a single, uni-directional F effect. No
ortho or alkyl. substituents are present in this set of 196 solutes. Using
the p and a constants Table 1 (see Methods), Eq. (7a) was derived by
regression:
OLP = 0.993(±0.018)ALP + 0.921(±0.075)p1o1 (7a)
+ 0.007(±0.044)
n = 187; s - .0976; r2 0.986
It is apparent that this equation meets the requireoents that the
coefficients of the (ALP) and (pa) terms be close to 1.0 and the intercept
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12
close to 0.0. In this and all regression equations which follow, n = the
number of data points in the regression, s = the standard deviation from
the regression, r2 = the square of the coefficient of regression (also =
fraction of the variance "explained" by the equation), and the numbers in
parentheses are the 95% confidence limits on each coefficient.
A reasonable estimate of average experimental error for the partition
coefficients used is ±0.05 (in log units), and so any simplified
calculation method which results in a standard deviation less than twice
this amount is worthwhile, especially since its incorporation into a
computer algorithm becomes entirely feasible. The simplifications which
were used in this and the following equations which include TQ are four:
1) use of a single electronic parameter for o^, m-, and .£- interactions; 2)
assignment of most substituents either to an I or an R class; 3) use of
generalized substituent structures, each member of a class being assigned
the same p or o value; 4) treating the halogens as a .single class (except
for the FO of fluorine as noted in Table 3).
Eq. (7a) can be compared to Eq. (7b) which has no F term:
OLP - 0.888(±0.032)ALP + 0.464(±0.045) (?b)
n 187; a - 0.20; r2 - 0.942
Solute #163 in Eqs. (7a) and (7b) was dropped from the regression because
it was out of line with the higher hoaologs, #164-167. Solute #58 probably
requires a special effect for alkoxy adjacent to a fused nitrogen, as do
#382 and #383 in a later subset. Solute #112, a phosphate ester, probably
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13
requires a small bond correction for alkyl chains beyond methyl. There is
no apparent reason to consider the other data points dropped (#11. #60,
#87, #96, #128,. #154) as representative of effects as yet unaccounted for
until repeat measurements confirm data reliability. Even when all the data
points are retained,as in Eq.(7c), the interpretation remains the same as
in Eq. (7a):
OLP - 0.975(±0.021)ALP + 0.849(±0.088)plOl (7c)
* 0.054(±0.051)
n <= 196; s = 0.118; r2 = 0.979
The use of generalized substituent structures (Table 1) has some
important implications for solvation theory as well as being advantageous
because of simplicity. As noted above, H-bond donating ability appears to
be an important criterion for a substituent's responsiveness to electronic
enhancement of hydrophobicity. The substituents with the highest p values
(-NH- = 1.08; -OH = 1.06) have this parameter reduced by one-half if the
hydrogen(s) on the hetero atom is replaced. In the case of -KH-, the H-
donating can be "insulated" from the ring by an electronegative group and
still retain a relatively high p value, as shown by -SO-NH- => 0.88 and
-C(=0)NH- - 0.72. This is not true for -OH since -COjH becomes much like
-C(=0)- (p » 0.35 and 0.27, respectively). It is also worthy of note that
with its remaining bond, -KH- can be attached to an electron-releasing
group such as CH3 or NH2, or to an electron-attracting group such as
carbonyl or -S02CF3, and the same p value persists. It would seem that the
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14
presence of the donatable hydrogen atom is inportant rather than its
acidity. Even when it has no attached hydrogen atoms to act as donors, the
nitrogen atom (as compared to oxygen) appears to promote values for the
groups which contain it: -N< = 0.61 vs. -0- = 0.50; -C(=0)N< = 0.6 vs.
-C(=0)0- =0.27.
Optimization of Hammett sigma constants to the data one has at hand has
been previously proposed zk 2S, but there is an understandable resistance to
the undue, proliferation of special sets.26 Unlike the usual Haniaett model,
however, where the substituent is at some distance from the reaction
center, the partitioning process is a solvation equilibrium where each
substituent IS a reaction center. Other evidence that the relative
solvation energy between octanol and water may, indeed, call for a modified
a parameter comes from the Hammett treatment of pKas in mixed solvent
97
systems. ' The usual Hammett as are excellent parameters for prediction up
to 80-85% organic solvent, at which point the standard deviation rises
markedly. In water-saturated octanol (2% water) the electronic influence on
solvation may not exactly follow the usual Hammett model systems. If Eq.
(7a) is recalculated with accepted a and a values, the standard deviation
is increased by 10% (to 0.1084). This is deemed sufficient reason to use
the optimized set in the computer program. A qualitative comparison of the
partitioning-optimized as with the classical Hamnett values discloses no
obvious trends. Those which remain essentially unchanged are: -CF,,
-CO-H, -CONH-, and the halogens. Those which are lower for F are: -N00
* O 2
and -S02~ (F, Alk, or N<). Those which are higher are: -CN, -N=, -C(=0)-,
and -CHO.
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15
As is seen in Table 1, six of the common substituents have significant
values of both p and o and thus must be classed I/R. The solutes in Table
5 showing this I/R effect(#197-£223) have a second o entered in column 9
and p in 10. When these 26 are added to the 187 solutes in the simple F
set of Eq. (7), the following regression equations are obtained:
OLP = 0.971(±0.018)ALP + 0.854(±0.078)plOl (8a)
+ 0.666C+0.042)
n - 213j a = 0.108; r2 = 0.983
OLP 0.991 (±0.017)ALP + 0.925(±0.074^0! (8b)
+ 1.144(±0.334)p2ff2 + 0.006(±0.042)
n - 213; s 0.0976; r2 - 0.986; F = 39.5
1 210
The larger 95% confidence limits on the "reverse" electronic term, f>2°2>
in Eq. (8b) clearly indicate that the available data do not characterize it
as well as they do the "forward" term, but its significance is well
established by the F test, and the coefficient does not differ
significantly from unity.
The attenuation of electronic effects on an adjacent fused ring
depends a great deal upon the relative contribution of Field and Resonance
components. All but one of the examples presently in hand are limited to
-N- as the Indueer, as seen in Table 2. For the R substituents -NH ,
-NHCOCH-, -OCH_, and -COCH- it seems appropriate to reduce the p value by
one-half. An exception is the dimethylamino substituent which apparently
responds unattenuated. Further studies on these and the di-substituted
naphthalenes are under way.
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16
Alkyl-Aryl Effect
The third subset from Table 5 to be analyzed(#224-#293) contains 70
solutes, each with the aromatic-aliphatic factor F . The regression
equation, dropping but one of these, is:
OLP - 0.984<±0.018)ALP - 0.159(±0.03)F (9a)
c
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17
A further snail but consistent effect is seen in solutes with alkyl
chains of length 3 or more.* When no aromatic ring is present, alkyl chains
display a steady hydrophobic increment of +0.54 per Ctt unit. With alkyl-
aryl combinations, this appears to be reduced to 0.49. A physical
rationale for this observation is not obvious. Dropping these solutes from
Eq. (9a), the following equation is obtained:
OLP - 0.992(±0.017)ALP - 0.171(±0.028)F . (9b)
019
+ 0.035(±0.041)
n = 65; s - 0.059; r2 = 0.997
Ortho Effects
As discussed in the Methods section, the total effect of ortho
substitution can be composed of three components: 1) an electronic effect,
Fff, considered as equal to that of raeta or para; 2) a negative effect,
which may in part stem from decoupling via twisting, and in part to a
reversal of the field effect if two polar substituents are in close
proximity; 3) a positive effect when certain types of intramol H-bonds can
occur, i.e., F^. It is convenient to apply the F in any case, but
o
* It should be noted that the direct determination of ir-values for n-alkyl
chains of three or more carbon atoms presents some experimental problems.
The only value for n-propyl benzene was determined by counter-current
extraction and HPLC. It is unexpectedly low. No values for the higher
homologs are available. On the other hand, i-propyl- and t-butyl-banzene
partition coefficients have been confirmed by two laboratories and, like
toluene, can be calculated reasonably well from separate alkyl-aryl
components by the fragment procedure: log P^j/* log P(i-butane) -2f# + Fj,
* Fc5j?=4.18; obsv. = 4.11. Since ir-constants were unavailable for the n-
butyl and n-pentyl substituents, ALP was calculated by adding the 0.54
increment for each methylene unit to the u-CH- taken from toluene.
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18
whenever F^ is called for, it should include ALL the remaining ortho
effect.
H-Bonding
When 15 solutes (#294-#308) containing an octanol-sensi'tive intramol H-
bonds are added to the original Ffl subset, the following regression
equation is obtained:
OLP = 0.994(±0.017)ALP + 0.93Q(±Q.Q71)Plai (10)
+ 0.63(±0.055)Ffl5 + 0.003(±0.04)
n - 201; s - 0.098; r2 = 0.987
Except for one solute (#303), F#B appears restricted to a carbonyl
moiety functioning as H-acceptor and either -OH or -NH- acting as H-
donor. Both "halves" must be attached directly to the ring, but the -NH-,
as noted for _Fff, may be followed either by a strongly electronegative
moiety, such as carbonyl, or an electron-releasing group such as methyl or
amino. The one outlier, o-hydroxybenzamide (#306), needs an even larger
correction (i.e., 0.63 + 0.34), indicating that a continuous function for
*BB may eventually be required as a greater variety of ortho substituents
are included in the data set.
If fBB is the actual source of the +An in o-nitroaniline (#303), it
would appear that both hydrogens on the nitrogen are necessary, because N-
methyl-^-nitroaniline (#343) and .o-nitroacetanilide (#342) do not show this
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19
AH- And the fact that .o-nitrophenol (#391) also does not need correction
raises the question of whether a nitro group can participate in an intramol
H-bond which is solvated differently by octanol vs. water. However, it
there is evidence that thiocarbonyl, as well as carbonyl, can act as an
octanol-sensitive H-acceptor. Assuming the o of the thioamide group in o-
aminothiobenzamide (log P = 0.99) to be slightly lower than the oxygen
analogue (#307), this would still leave a factor of about +0.45 to be
accounted for by something like Fgg.
Negative Ortho Effect
There is no compelling reason to believe that non-H-bonding ortho
effects should be "quantized" rather than being better represented by a
continuous function. (However, for arguments favoring quantized effects in
hydrophobicity, see reference 5.) Nevertheless, for ease of computer
calculation it vas decided to approximate it as a multiple of a fixed
lowest level since attempts to rationalize it in terms of size (Es) and
field effect Cr) were no improvement (see Methods). In Table 3 the
appropriate interaction levels between the substituents are displayed in
matrix format. The regression equation for the 59 solutes(#309-369) in the
non-H-bonding subset is:
OLP - 0.982(±0.036)ALP + 1.117(±0.196)p1o1 (lla)
+1.747(±0.72)p2a2 - 0.304(±0.031)FO -0.019(±0.105)
n = 59; s - 0.085; r2 = 0.990
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20
Merging this set with the subset containing just FQ effects [Eq. (8b)J, the
four-variable equation becomes:
OLP = 0.988(±0.016)ALP + 0.943(±0.068)p1o1 (lib)
+ 1.228(±0.298)p2a2 - 0.289(±0.017)F + 0.002(±0.04)
o
n 272; s = 0.0958; r2 - 0.986;
Although far from complete, Table 3 contains a great deal of useful
information. For instance, substituents can be placed in an approximate
order of their ability to cause an F : -CONH-, -HHCOCH >-CO H, -SO NH-,
-NHCONH2>-C02->I,Br,Cl> F,N02>-0-, -OH> NH . Of course these distinctions
may not apply in all pairings. For instance, Cl> NO , when paired with
S02NH-, -C02H, -OH, and^-NHCOCI^, but Cl - KO^ for -CO- and -0-. The
most glaring anomaly is the alkoxy-aiaido pairing (solute #209). It
requires no F^ although, fron a comparison with the carboxyl-, carbonyl-,
and halogen-alkoxy pairings, one would be expected. Since
2-methoxybenzoylhydrazine behaves as expected (#354; F » 1), it is
possible that the substituent -CONH-X cannot be generalized in a way that X
= either H or NH2. There are insufficient data to characterize an ortho
~N(CH3)2J but the fact that no factor is required with methyl adjacency is
surprising (#280).
An effort is under way to fill in the blank spaces in Table 3 and to
characterize the effect of 2,6-disubstitution. In the meantime, it is
likely that calculations of log P using interpolated values (in italics in
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21
Table 3) would be more accurate than calculations ignoring this effect
altogether. Interpolation was done keeping in mind the likelihood that
both Es and ^ play a role.22 ThuSjin the halogen serieSf where the
field effects remain nearly constant, but the size varies from fluorine up
to iodine, the remainder of the series can be estimated when the effect of
only one member is known. The methyl group lacks a positive field effect,
but is the same size as a bromide. Thus one expects it to have a lower
effect, as is noted when each is paired with -CO H.
It should be noted that the range of measured solutes represented by the
generalized structures shown in Table 3 is not as great as in Table 1.
Note also that in Table 3 -NHCONH2 must be separated from -NHCOCH .
However, since the Es parameter depends greatly on the bulk close to the
attachment atom,28 and the field effect may in this case operate only over
very short- distances, it is a reasonable expectation that much of the
generality implied in Table 3 will be supported, and the symbols 'V, 'Z^
and 'Zj1 will then represent more than one substituent each.
Multiple I and R Effects
In the above treatment of disubstituted aromatic solutes, the correction
factors fgt FO, Fflfl, and F combine to reduce the deviation between the
observed log P and the "simple additive" log P by a factor of 3 or better.
For many applications this improvement could be vital. But an even greater
need for correction arises when the solute contains multiple "I" or "R"
groups. In many cases, as will be seen below, All is greater than 2 log
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22
units, and uncorrected calculations would be entirely misleadicg. The
problem is complicated by the fact that for calculating hydrophobicity, the
o parameters are not truly additive as they are in the ideal Kanuaett
application. Furthermore, the classic Hammett applications do not envision
the use of more than one P in any given expression. From an examination of
just the multi-chlorinated aromatics it would seem that the electronic
effect upon a polar substituent by a second chlorine was only half as great
as the first, and all further chlorines could be added without considering
an electronic effect at all. On the other hand, the p values of multiple R
substituents might best be either added or averaged, depending upon the
particular Inducer present.
To study the effect when two or more Inducers are present with a single
Responder, the ideal solutes would appear to be anilines or phenols
substituted in the 3-, 4-, and/or 5-positions with N02, CF3, S02F, or
the halogens. Substitution in the 2- position can be accepted to
enlarge the set since allowance can be made for F . Unfortunately,
there are no data for the di-CF3 , the di-S02F compounds, or the
dinitroanilines. The di- and trinitrophenols are anomalous when
partitioned in 0.1N HC1 to suppress ionization (log P (picric ac.)=
0.89). Quite a few multi-halogenated phenoxyacetic acids have been-
measured, but they are not considered suitable for analysis of this effect
for two reasons: the value for the -0-X substituent is low, making the
system rather insensitive, and also there was no effort to suppress
ionization in these measurements. There is no way of making sure 'that the
-------
23
electronic effect on pKa (i.e. the ratio of neutral to ionized solute) is
not interfering with the desired observation of purely hydrophobia effects.
This leaves a rather limited set of halophenols, haloanilines,
halobenzaaides, and haloanthranilic acids which appear in Table 4. From
this set can be drawn the tentative conclusion that the effect diminishes
with the number of "I" groups so that the coefficient for the E0 follows
the series: 1.0; 0.75; 0.60; 0.35. It will be noted that in solutes
#10-13 in Table 4, where an R and I/R substituent appear together, the o
values are averaged. Other examples of averaging P values for multiple
occurrence of R groups are £315, £361, £382, £383, and £385-389 in Table 5.
In contrast to the examples just cited, an aromatic nitrogen (-N=)
appears to affect multiple responders on its ring at "full strength"; i.e.,
their rhos are added, not averaged. As multiple "I" groups, however, the
attenuaton of 0 for -N= follows the same series illustrated in Table 4.
The only examples in the present data base are those where the multiple "R"
groups are amino and the multiple "I" groups are -N=; i.e., ami'no
substituted pyrimidines and sym-triazines. The following calculations
would indicate that there may be a maximum value for F of 2.8:
-------
24
ALP » log P pyrimidiae + 2 II + H
0.40 +2 (-1.23) + 2.01
Fff = (n=2)coef. Za Zp
(0.75) x (.84 + .84) x (1.08 + 1.08) = 2.72
(C-l)
= -0.85 +
obsv. = 1.58 calcd - 1.87
ALP - log P triazine + 3
-0.73
HN(Me).
Fff = (n=3)coef.
+ 3(0.18)
la Zp
(0.6) x 3(0.84) x 3(0.61)
obsv. = 2.73
(C-2)
-0.19 +
2.77
calcd = 2.58
-------
25
ALP - log P triaziue + 3
-0-73
F = as C-2
N(Jfe)Et
+ 3(0.64)
(c_3)
obsv. = 3.90
calcd
1.19
2.77
3.96
log , tria,iae * ^^ «. ^ (c,4)
-0.73 + 2(0.18) + (-0.47) - -0.84 +
0.6(3)(0.84)(1.08 + 0.61 + 0.61) ] » (3.48)
Cake max F = 2.80
o
obsv. - 1.83
calcd
1.96
-------
26
*9
/We Vie
ALP = log P triazine * 2 H,^ + n^ (C-5)
-0.73 + 2(0.18) + (-1.23) - -1.60 +
FO - as C-4 = 3.48; take max Fff = 2.80
obsv. - 1.20 calcd = 1.20
Groups on Insulating Side-Chains
There is a positive An for an I-R interaction even when the Responding
substituent is not directly attached to the ring but is instead on a
benzyl carbon atom. This lower but significant Fff indicates that the
field effect29 must play an important role. The data now in hand are
insufficient to determine whether the attenuation is equal for all groups
listed in Table 1. A factor of 0.6 has been applied to the p values of
solutes #393-397 and #401 with reasonably satisfactory results. The
reverse interaction, where the "I" substituent is on the benzyl carbon and
the "R" is attached to the ring, appears to need no correction factor.
Thus,the log P for m- and £-hydroxyphenylacetic acids are 0.85 and 0.75,
respectively. The "simple additive" log P is 0.74, and so it would appear
-------
27
that no more than 15% of the "directly-attached" effect was transmitted.
In the case of m- and jrmethoxyphenylacetic acids, both groups are I/R and
the "simple additive" log P is only 0.1 lower than the observed values,
which are 1.50 and 1.48, respectively.
If th6 role of resonance in the electronic enhancement of log P were
dominant, one would predict that substituents on the styryl carbon atom
would interact stongly with others on the ring. This appears to be the
case for a N0£ group on the styryl carbon, as the following examples
indicate:
OLP ALP p 0
3-methoxy-B-nitrostyrene 2.37 2.09 (.5)x(.6) - 2.39 (c-6)
4-methoxy-g-nitrostyrene 2.20 2.09 (,5)x(.6) - 2.39 (C-7)
3-hydroxy-g-nitrostyrene 2.07 1.44 (1.06)x(.6) = 2.08 (C-8)
4-hydroxy-fr-nitrostyrene 2.12 1.44 (1.06)x(.6) = 2.08 (C-9)
The data for substituted cinnamic acids, on the other hand, cannot be
interpreted directly in this fashion. The 4-hydroxy and
3,4-dimethoxycinnamic acids (log P = 1.79 and 2.34, respectively) need no
Fo, to correct the "simple additive" log P, while the pff values from Table 1
seem to apply well for the 4-methoxy and the 4-hydroxy-3-methoxy analogues
(log P = 2.68 and 1.87, respectively).
The final subset in Table 5, solutes #369-401, include examples of mixed
and multiple Factors. The p and o values from Table 1 were used with
-------
28
adjustments appropriate to the methods discussed above. The overall
regression equation, dropping 15 data points for reasons discussed above,
is:
OLP - 0.986(±0.012)ALP + 0.916(10.054^0! (12a)
0.970(±0.21)p2o2- 0.285(±0.016)F0 + 0.626(±0.053)Ffi5
- 0.153(±0.022)F A + 0.020(±0.029)
019
n = 386; s =0.0955; r2 - 0.990
If all the data points are used, the statistics are affected, but there
is no significant change in the values for the Factors which are derived:
OLP = 0.972(±0.013)ALP + 0.900(±0.06)plOl + (12b)
+ 0.859(±0.24)p2o2 - 0.281(±0.019)F^ + 0.643(±0.059)FDD
O OO
-0.137(±0.025)F . + 0.044(10.034)
a 9
n » 401; s = 0.112; r2 = 0.986
If no correction factors are employed, the observed log P and "simple
additive" log P are related as:
OLP - 0.811(±0.03)ALP + 0.465(±0.054) (12c)
n = 386; a = 0.324; r2 = 0.881
Comparing Eq. (12a) and (12c), we can judge the significance of the five
correction terms (four, if PiO! and P2a2 are combined as FQ) by an F test:
F = 810.
5 379
-------
29
Giving more veight to the earlier equations from the subsets dealing
with the least variety of factors, the preferred values are:
F = Pi0!* p2°2 with P and cr values taken from Table 1
= +0'63
- -0.28
The author wishes to acknowledge generous financial assistance from the
U.S. Environmental Protection Agency contract 68-01-5043 through Battelle
Columbus Laboratory subcontract T-6415(7197)-029 and a grant from ERL-
Duluth No. CR 809295-01-0. Technical assistance in partition coefficient
measurements by Mrs. P. C. Jow, Mr. Tommy Chan and Mr. George Gould and
help in gathering and analyzing data Dr. Corwin Hansch is also greatfully
acknowledged.
-------
1. W. Nernst, Z. Phys. Chem., 1891, 8, 110.
2. A. Leo, C. Hansch and D. Elkins, Cliem. Rev., 1971, 71, 575.
3. C. Hansch and A. Leo, 'Substituent Constants for Correlation Analysis
in Chemistry and Biology', Wiley Interscience, New York, 1979.
A. S. Yalkowsky, A. Sinkula and S. Valvani, Eds., 'Physical Properties of
Drugs', Marcel Decker, New York and Basel, 1980, Ser. No. 10, Chpts. 3,5 &6.
5. R. Rekker, 'The Hydrophobia Fragcnental Constant', Elsevier Sceintific,
Amsterdam, 1977.
6. (a) Y. Martin. 'Quantitative Drug Design', Medicinal Research Series No. 8,
Marcel Decker, New York and Basel, 1978. (b) P. Hagee, Chemtech, 1981, 11,'
378. (c) R. Smyth, M. Pfeffer, D. Van Harken, A. Cohen and C. Hottendorf,
Antimicrob. Agents Chertother., 1981, 19, 1004. (d) D. Koblin, E. Eger Il[
B. Johnson, P. Collins, R. Terrell, and L. Spears, Anesth. Analg., 1981, 60,
464. (e) D. Brown and E. Flagg, J. Environ. Qual., 1981, 10, 382. (f)
H. Ellinghausen, J. Guth and H. Eser, Ecotox. Environ. Safety, 1980, 4, 26.
(g) H. Levitan, Pros. Natl. Acad. Sci. USA, 1977, 74, 2914. (h) W. Neeley,
D..Branson and G. Blau, Environ. Sci. Technol., 1974, 8, 1113. (i) c.
Tanford, 'The Hydrophobic Effect', John Wiley, New York, 1980, 2nd. Ed.,
Chpt. 13. (j) E. Coats, G. Genther, S. Dietrich, Z. Guo and C. Hansch,
J. Med. Chem.., 1981, 24, 1422-. (k) R. Smith, C. Hansch and R. Langridge,
Arch. Bioehen. Biophys., 1982, 215, 319. (1) K. Martinek and A. Semsnlv,'
JT. Appl. Biochem., 1981, 3, 93. (m) M. Newcomb, S. Moore and D. Cram,. '
cT. Am. Chem. Soc.f 1977, 99, 6405.
7. C. Hansch, P. Maloney, T. Fujita and R. Muir, Nature, 1962, 194, 178.
8. R. Cramer III, J. Am. Chem. Soc.f 1977, 99, 5408.
9. L. Hacnnatt, 'Physical Organic Chemistry: Reaction Rates, Equilibria and
Mechanism1, McGraw-Hill, New York, 1970, 2nd. Ed.
10. T. Fujita, J. Iwasa and C. Hansch, J. Am. Chem. Soo.f 1964, 86, 5175.
11. T. Fujita, J. Pharm. Sci., in the press.
12. T. Fujita, Prog. Phys. Org. Chem., in the press.
13. Ref. 6(a), p. 74.
14. J. Iwasa, T. Fujita and C. Hansch, «T. Med. Chem., 1965, 8, 150.
-------
15. A. Leo, C. Hansch and P. Jow, J. Med. Chem., 1976, 19, 611.
16. Pomona College Hedchera Project, Claremont, CA, USA, 91711; Issue §21.
17. E. Smith and P. Baker, 'The Wiswesser Line-Formula Chemical Notation (WLN)'
CIMI, Cherry Hill, NJ., 1975, 3rd. Ed.
18. J. Chou and P. Jurs, J. Chem. Inf.. Cornpb. Sci., 1979, 19, 172.
19. Written in APL by Steven Burns, Pomona College.
20. K. Bowden, N. Chapman and J. Shorter, J. Chem. Soc., 1964, 3370.
21. R. HcKeown, J. Chem. Soc., Perkin Trans., 1980, 515.
22. A. Ogino, S. Matsumura and T. Fujita, J. Med. Chem.., 1980, 23, 437.
23. V. Austel, Arzneim. Forsch., 1979, 29, 585.
24. M. Sjostrom and S. Wold, Chem. Script., 1976, 9, 200.
25. S. linger and C. Hansch, J. Med. Chem.* 1973, 16, 745.
26. C. G. Swain and E. Lupton, 3. Am. Chem. Soc., 1968, 90, 4328.
27. J-C. Halle and R. Schull, Anal. Chem. Acta., 1972, 60, 197.
28. S. Unger and C. Hansch, 'Progress in Physical Organic Chemistry1, R. Taft,
Ed., Wiley Interscience, New York, 1976, p. 91.
29. Y. Yukawa, Y. Tsuno and M. Sawada, Bull. Chem. Soc. Jpn., 1972, 45, 1198.
-------
TABLE 1.
Sigma and Rho Constants
No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Sigma Rho Generalized Structure
0.84 0.00
0.71 0.00
0.65* 0.00
0.65 0.00
0.60 0.00
0.49 0.00
0.28 0.00
0.58 0.44*
0.51 0.27
0.32 0.35*
0.32 0.72
0.17* 0.50*
0.50C 0.88°
d d
0.00a 0.50a
0.00 0.61
0.00 1.06
0.00 1.08
-N=
-S02F
-so2-x
-CN
-NO
-°F3
Halogens
-CHO
-C(=0)-X
-C02H
-CONH-X
-0-X
-SO,NH-X
2
-S-X
-N<
-OH
-NH-X
Examples
pyridine, quinoline
X = alk, N(Me)2
F, Cl, Br, I
X t M 1 1. f\f*V f* U M f \ff«*\
**^**> *JwQo > ^*.£**c > *^ vWe } o
X = H, NH_, C.H-, alk
t. O J
X = alk, CONHCH., CON (Me),,
CH2C02H, POtO-alk)2 2
X = H, C-H-
6 5
X = H, alk
-N(Me)2, -N=NN(Me)2
X = COMe, CON (Me) CHO, alk,
pnivnjf* H f u en r>v
\*\jinn\*stt. ~ i^^n^. 2U_ur
_____ 6565 23
* Not determined by successive approximation program.
a. Effect cut in half for Responders on non-hetero ring.
b. With original training set of 90 solutes, 0.51 was obtained. With the set
enlarged with bi-directional solutes, 0.50 gave coefficients for the F term
a
closer to unity.
C. Acts either as 'I* or 'R1 but not both at the same time; i.e. it is not
truly bi-directional; exception is solute #208 in Table 5.
d. Not well characterized; should be considered tentative.
-------
32
TABLE 2.
Attenuation of Electronic Effect, F
o
In Adjacent Fused Ring
1.
2.
3.
4.
5.
6.
7.
8.
9.
Compound
5-aminoquinoline
6-aminoquinoline
6-acetylaraino-
quinoline
6-methoxyquinoline
7-methoxyquinoline
6-acetylquinoline
1-aminoacridine
7-dimethylamino-
quinoline
l-ditnethylaraino-5-
sulfonamido-
naphthalene
Obsv.
Log P
1.16
1.28
1.55
2.20
2.37
1.58
2. 47
2.71
2.01
Add.
Log P
0.80
0.80
1.06
2.01
2.01
1.48
2.17
2.21
1.66
Sigma
0.84
0.84
0.84
0.84
0.84
0.84
0.84
0.84
0.50
One-Half
Rho*
0.54
0.54
0.54
0.26
0.26
0.13
0.54
0.25
(0.50)
0.25
(0.50)
Calc.
Log P
1.25
1.25
1.51
2.23
2.23
1.59
2.62
2.42
(2.63)
1.79
(1.91)
Dev.
+0.09
-0.03
-0.04
+0.03
-0.14
+0.01
+0.15
-0.29
(-0.08)
-0.22
(-0.10)
*Examples of 2-, 3-, and 4-substituted quinolines with full rho values
can be found in Table 5. Values in parenthesis for dimethylamino
analogs have full rho values.
-------
TABLE 3.
Ortho Factor Levels
33
g
1^1 ^^^ ^^^
*-* rH CM
wiPco 5 S ^3
O) Z ^-* SC I I CM CO CU C9
OOIOWW33SCPBWI |
uuocowogsjszov-w
tnvor^oootOi-icM
iHt-liHt-lrHeMeMeM
\
11 01
0
3 1
2 0 (0) 1
0)
0
0
0
1 2
1 2
12300
1 1
2,
\5 Ot
\0
W = OMe, He, N(Me)2
X = H, NH2
Y = CONHMe, COMe,Me,CON(Me)
OCH2C02H
If CONHg . :_
Z2= COMe ...
*This level becomes 5 if Y = C,HC
" ° *
( )= borderline effect
Within submatrix,'Hydrogen Bonds', F =0; F =1
I. O Ho
t = anomalous; see text
Italicized numbers are interpolated.
,Intra-Mol.
HYDROGEN
0,' BONDS
i
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
20.
21.
22.
-------
34
TABLE 4.
Multiple Electronic Effects
Solute
1. 2,3-dichloroaniline
2. 3 > 4-dichloroaniline
3. 2,4-dichlorophenol
4. 3,5-dichlorophenol
5. 2,4-dibromophenol
6. 3,5-dinitrobenzamide
7. 2-aminopyrimidine
8. 2-aminopyrazine
9. 2,6-dinitro-4-CF3-
aniline
10. 3-iodo-4-amino-
benzoic acid
11. 3-bromo-4-ami.no-
benzoic acid
12. 3-chloro-4-amino-
benzoic acid
13. 4-fluoro-4-amino-
benzoic acid
14. 2,3,4,6-tetrachloro-
phenol
OLP
2.
2.
3.
3.
3.
0.
-0.
78
78
08
44
22
83
2
2
2
2
3
0
22-1
ALP
.32
.32
.88
.88
.18
.12
.63
-0.07-1.45
2.
29
1.26
Fo
.75(.28
.75(.28
75(2)(.
75(2)(.
.75(2) (.
.75(2)(.
-75(2)(.
75(2)(.
+ .28) (1.08)
+ .28) (1.08)
28) (1
28) (1
28) (1
.06) -.28*
.06)
.06)-. 28*
6) (.72)
84) (1
84) (1
.08)
.08)
.6 (.60+. 60+. 49) (1.08)
Calc.
2
2
3
3
3
0
-0
-0
2
.77
.77
.05
.33
.34
.77
.27
.09
.35
Dev.
+.01
+.01
+.03
+.11
-.12
+.06
+.05
+.02
-.06
1.65 1.99 .75(.28+.32)(1.08+.35)*2
-2(.28)* 1.75
1.49 1.73 (as #10.)
1.33 1.58 (as #10.)
1.49
1.34
1.2971.01 .75(.28+.32)(1.08+.35)*2
-.28* 1.05
4.10 4.30 .35(4)(.28)(1.06)-2(.28)*4.16
-.10
0.0
-.01
-.24
-.06
* F ; see text and Table 3.
-------
to
O^erved Partition Coefficients and Parameters for Aromatic Solutes
SOLUTE
1 BR-PH-3-OCONHCH3
2 BR-PH-4-NHCOCH3
3 BR-PH-4-OCONHCH3
4 BR-PH-4-COCH3
5 F-PH-3-OCONHCH3
6 F-PH-4-NHCOCH3
7 F-PH-4-OCONHCH3
8 F-PH-4-OCOCH3
9 F-PH-4-COCH3
10 GF3-PH-3-NHCON(ME)2
ll*CF3-PH-3-NHCOCH3
12 CF3-PH-3-OCONHCH3
13 CF3-PH-3-OCOCH3
14 CL-PH-3-COCH3
15 CL-PH-4-NHCOCH3
16 CL-PH-4-OCOCH3
17 NC-PH-3-OCONHCH3
18 NC-PH-3-COCH3
19 NC-PH-4-OCONHCH3
20 NC-PH-4-COCH3
21 HO-PH-3-CN
22 HO-PH-3-BR
23 HO-PH-3-F
24 HO-PH-3-CL
25 HO-PH-3-I
26 HO-PH-3-C02CH3
27 HO-PH-3-COCH3
28 HO-PH-3-CF3
29 HO-PH-4-CN
30 HO-PH-4-BR
31 HO-PH-4-F
32 HO-PH-4-CL
33 HO-PH-4-I
34 HO-PH-4-OCH3
35 HO-PH-4-C02CH3
36 HO-PH-4-COCH3
37 HO-PH-4-COET
38 CO2H-PH-3-CN
39 CO2H-PH-3-BR
40 C02H-PH-3-F
41 C02H-PH-3-CL
42 C02H-PH-3-I
43 C02H-PH-3-OH
44 CO2H-PH-3-CF3
45 CO2H-PH-4-CN
46 CO2H-PH-4-BR
47 CO2H-PH-4-F
48 CO2H-PH-4-CL
49 CO2H-PH-4-I
0
L
P
tt
2.25
2.29
2.17
2.43
1.48
1.47
1.28
1.74
1.72
2.36
2.20
2.37
2.63
2.51
2.05
2.01
.97
1.16
.95
1.22
1.70
2.63
1.93
2.48
2.93
1.89
1.39
2.95
1.60
2.65
1.79
2.40
2.92
1.39
1.96
1.30
2.03
1.48
2.87
2.15
2.68
3.13
1.50
2.95
1.56
2.86
2.08
2.65
3.02
A
L
P
t
2.07
2.02
2.07
2.40
1.35
1.30
1.35
1.63
1.72
1.86
2.04
2.09
2.37
2.29
1.87
1.92
.64
1.01
.64
1.01
.89
2.32
1.60
2.17
2.58
1.44
.91
2.34
.89
2.32
1.60
2.17
2.58
1.39
1.44
.91
1.45
1.30
2.73
2.01
2.58
2.99
1.20
2.75
1.30
2.73
2.01
2.58
2.99
S
I
G
1
.28
.28
.28
.28
.28
.28
.28
.28
.28
.49
.49
.49
.49
.28
.28
.28
.65
.65
.65
.65
.65
.28
.28
.28
.28
.51
.51
.49
.65
.28
.28
.28
.28
.17
.51
.51
.51
.65
.28
.28
.28
.28
.32
.49
.65
.28
.28
.28
.28
R
H
0
1
.50
1.08
.50
.27
.50
1.08
.50
.50
.27
1.08
1.08
.50
.50
.27
1.08
.50
.50
.27
.50
.27
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
1.06
.35
.35
.35
.35
.35
1.06
.35
.35
.35
.35
.35
.35
0
R
T
H
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
H
B
N
D
0
0
0
0
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-------
PAGE 2
50 C02H-PH-4-NHCOCH3
51 C02H-PH-4-OH
52 H02CCH20-PH-3-CM
53 H02CQI20-PH-3-C02H
54 H02CCH20-PH-4-CN
55 HS-PH-2-C02H
56 ACRIDINE-9-NH2
57 PYR-2-NHCOCH3
58*PYR-2-OCH3
59 PYR-3-NHCOCH3
60*PYR-3-OH
61 PYR-3-CONHC6H5
62 PYR-3-CONH-I-PR
63 PYR-3-CONHCH3
64 PYR-3-C02CH3
65 PYR-3-C02ET
66 PYR-3-COC6H5
67 PYR-3-CCWH2
68 PYR-3-COCH3
69 PYR-3-NH2
70 PYR-4-NHCOCH3
71 PYR-4-N(ME)2
72 PYR-4-OCH3
73 PYR-4-CHO
74 PYR-4-CONHNH2
75 PYR-4-CO2CH3
76 PYR-4-CO2ET
77 PYR-4-COC6H5
78 PYR-4-COCH3
79 PYR-4-NH2
80 QUIN-4-NHCOCH3
81 QUIN-4-NH2
82 QUIN-5-NH2
83 QUIN-6-NH2
84 QUIN-7-NHCOCH3
85 QUIN-7-NH2
86 NC-PH-4-NHCHO
87*CH3CO-PH-4-NHCHO
88 CHO-PH-3-OH
89 CHO-PH-3-CF3
90 CHO-PH-4-N(HE}2
91 CHO-PH-4-OR.
92 N02-PH-3-NHCHO
93 N02-PH-3-NHCOCH3
94 N02-PH-3-N02
95 N02-PH-3-OCONHCH3
96 *N02-PH-3-OCOCH3
97 NO2-PH-3-OCH3
98 NO2-PH-3-OCH2C02H
99 N02-PH-3-OH
00 N02-PH-3-CHO
01 N02-PH-3-CO2ET
02 N02-PH-3-CO2H
03 NO2-PH-3-COCH3
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-------
PAGE.3
104 N02-PH-3-CF3
105 N02-PH-4-NHCHO
106 N02-PH-4-NHCON(HE)2
107 N02-PH-4-KHCOCH3
108 N02-PH-4-NHCH3
109 N02-PH-4-N02
110 N02-PH-4-N(HE)2
111 K02-PH-4-OPO(OME) 2
112*N02-PH-4-OPO(OET)2
113 N02-PH-4-OCONHCH3
114 N02-PH-4-OCON(ME)2
115 N02-PH-4-OCOCH3
116 N02-PH-4-OCH3
1.17 N02-PH-4-OCH2CO2H
118 N02-PH-4-OH
119 N02-PH-4-CHO
120 N02-PH-4-C02ET
121 N02-PH-4-C02H
122 N02-PH-4-COCH3
123 FS02-PH-4-NHCOCH3
124 FSO2-PH-4-OCH2CO2H
125 CH3S02-PH-3-NHS02CF3
126 CH3S02-PH-3-OCH3
127 CH3S02-PH-4-NHS02CF3
128*CH3S02-PH-4-OCONHCH3
129 CH3S02-PH-4-C02H
130 BR-PH-3-CONHKH2
131 CL-PH-3-CONHNH2
132 I-PH-3-CONHNH2
133 N02-PH-3-CONHNH2
134 HO-PH-3-CONHNH2
135 H2N-PH-3-CONHNH2
136 BR-PH-4-CONHNH2
137 CL-PH-4-CONHNH2
138 I-PH-4-CONHNH2
139 N02-PH-4-CONHNH2
140 HO-PH-4-CONHNH2
141 H2N-PK-4-CONHNH2
142 H2N-PH-3-CN
143 H2N-PH-3-CL
144 H2N-PH-3-N02
L45 H2N-PH-3-OCH3
L46 H2N-PH-3-CF3
L47 H2N-PH-4-BR
L48 H2N-PH-4-CL
L49 H2N-PH-4-I
.50 H2N-PH-4-NO2
.51 H2N-PH-4-SO2N(ME)2
52 H2N-PH-4-S02CH3
53 K2N-PH-4-C02ET
54*H2N-PH-4-CF3
55 H2NSO2-PH-3-CL
56 H2NS02-PH-3-N02
57 H2NS02-PH-4-CN
2.62 2.75
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-------
PAGE 4
158 H2NS02-PH-4-BR
159 H2NS02-PH-4-N=NN(HE)2
160 H2NSO2-PH-4-N(HE)2
161 H2NS02-PH-4-OCH3
162 H2NS02-PH-4-OH
16 3 *H2NS02-PH-4-CONHCH3
164 H2NS02-PH-4-CONHET
165 H2NS02-PH-4-CONHPR
166 H2NS02-PH-4-CONHBU
167 H2NS02-PH-4-CONHPEN
168 H2NS02-PH-4-C02CH3
169 H2NSO2-PH-4-C02ET
170 H2NS02-PH-4-C02PR
171 H2NS02-PH-4-C02BU
172 H2MS02-PH-4-COCH3
173 H2NS02-PH-4-NH2
174 H2NCONH-PH-3-BR
175 H2NCONH-PH-3-F
176 H2NCONH-PH-3-CL
177 H2NCONH-PH-3-CF3
178 H2NCONH-PH-4-BR
179 H2KCONH-PH-4-F
180 H2NCONH-PH-4-CL
181 H2NCONH-PH-4-OC6H5
182 CONH2-PH-3-CM
183 CONH2-PH-3-N02
184 CONH2-PH-3-N(ME)2
185 CONH2-PH-3-OH
186 CONH2-PH-4-CN
187 CONH2-PH-4-KHCOCH3
188 CONH2-PH-4-N=NN(ME)2
189 CONH2-PH-.4-N02
190 CONH2-PH-4-N(ME)2
191 CONH2-PH-4-OH
192 CONH2-PH-4-CF3
L93 CONH2-PH-4-NH2
194 CH3NH-PH-4-SO2N{ME}2
95 CH3CONH-PH-4-OCH3
96 CH3CO-PH-4-N(ME)2
197 C02H-PH-3-OCH3
98*C02H-PH-3-C02CH3
99 CO2H-PH-3-C02H
200 CO2H-PH-4-OCJI3
01 CO2H-PH-4-CQ2H
~02 CHO-PH-3-OCONHCH3
?03 CHO-PH-4-OCONHCH3
04 CHO-PH-4-OCH3
^05 CHO-PH-4-OCH2CO2H
"06 CH3O-PH-3-CONHNH2
07 CH30-PH-4-CONHMH2
^08 H2NSO2-PH-3-SO2NH2
39 CONH2-PH-2-OCH3
LO CONH2-PH-3-OCH3
211 CONH2-PH-3-CONH2
1.36
(ME) 2 1.06
)2 .76
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CH3 -.31
ET .03
PR .51
JU 1.05
PEN 1.51
O .64
C 1.17
i 1.75
J 2.34
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1.71
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1.66
1.96
2.00
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1.76
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1.21
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1.38
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1.69
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1.69
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1.09
1.80
1.80
1.85
1.61
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-------
PAGE 5
212 CONH2-PH-4-OCOCH3
213 CONH2-PH-4-OCH3
214 CH30-PH-3-CON(HE)2
215 CH30-PH-4-CON(ME)2
216 CH30CO-PH-3-OCONHCII3
217 CH30CO-PH-4-OCONHCH3
218 CH3OCO-PH-4-OCH3
219 CH3CO-PH-3-OCON(ME)2
220 CH3CO-PH-3-OCH3
221 CH3CO-PH-4-OCONHCH3
222 CH3CO-PH-4-OCOCH3
223 CH3CO-PH-4-OCH3
224 CL-PH-2-CH3
225 CL-PH-3-CH3
226 CL-PH-4-CH3
227 C6H11-PH-4-OH
228 NAPHTHYL-2-CH3
229 NAPHTHYL-2,3-(ME)2
230 NAPHTHYL-2,4-(ME)2
231 NAPHTHYL-2,5-(ME)2
232 NAPHTHYL-2,6-(ME)2
233 NAPHTHYL-2,7-(ME)2
234 HO-PH-2-CH3
235 HO-PH-2,4-(ME)2
236 HO-PH-2-ET
237 HO-PH-2-PR
238 HO-PH-3-CH3
239 HO-PH-3,4-(ME)2
240 HO-?H-3,5-(ME)2
241 HO-PH-3-ET
242 HO-PH-4-CH3
243 HO-PH-4-ET
244 C02H-PH-3-CH3
245 CH3-PH-3-OCH2C02H
246 T-BU-PH-3-OCH2C02H
247 I-PR-PH-3-OCH2C02H
248 ET-PH-3-OCH2C02H
249 PR-PH-3-OCH2C02H
250 BU-PH-3-OCET2C02H
251 CH3-PH-4-OCH2C02H
252 CH3-PH-3-CH2C02H
153 CH3-PH-4-CH2CO2H
J54 CH3-PH-3-CH20H
7.55 CH3-PH-4-CH2OH
{56 INDOLE-3-CH3
^57 INDOLE-5-CH3
»58 PYR-2-CH3
59 PYR-2,6-(ME)2
^60 PYR-3-CH3
"61 PYR-4-CH3
62 PYR-4-BU
263 QUIN-2-CH3
64 N02-PH-2-CH3
55 NO2-PH-3-CH3
13 .27
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3)2 1.00
2)2 .96
JHCII3 1.42
IHCH3 1.50
! 2.27
!ME)2 1.18
1.84
ECH3 1.01
13 1.29
1.74
3.42
3.28
3.33
4.22
3.87
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)2 4.42
)2 4.37
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1.95
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2.47
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3 1.78
2H 2.96
2H 2.59
2.25
2.71
3.18
I 1.86
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4.72
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2.78
2.66
3.20
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2.78
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2.66
2.53
1.92
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-------
PAGE 6
266 N02-PH-4-CH3
267 CH3-PH-3-CONHNH2
268 CH3-PH-4-CONHNH2
269 CH3-PH-2-KH2
270 CH3-PH-3-NH2
271 CH3-PH-4-NH2
272 CH3-PH-2-S02NH2
273 CH3-PH-3-S02NH2
274 CH3-PH-4-SO2NH2
275 CH3-PH-3-NHCONH2
276 CH3-PH-3-CONH2
277 CH3-PH-4-CONH2
278 CH3-PH-2-NHCH3
279 CE3-PH-4-NHCH3
280 CH3-PH-2-N(ME)2
281 CH3-PH-2-OCH3
282 CH3-PH-3-OCH3
283 CH3-PH-4-OCH3
284 CH3-PH-2-C02CH3
285 CH3-PH-2-CH3
286 1,2,4,5-(ME)4-PH
287 CH3-PH-3-CH3
288 CH3-PH-4-CH3
289 CH3-PH-NHCOCH3
290 CH3-PH-2-OCOCH3
291 CH3-PH-3-OCOCH3
292 CH3-PH-4-OCOCH3
293 CH3-PH-4-COCH3
294 HO-PH-2-CO2CH3
295 HO-PH-2-COCH3
295 HO-PH-2-C02ET
297 C02H-PH-2-NHG6H5"
298 CO2H-PH-2-NHCOCH3
299 HO-PH-2-C02H
300 HO-PH-2-CHO
301 HO-PH-2-CONHNH2
302 H2N-PH-2-CONHNH2
303 H2N-PH-2-M02
304 H2N-PH-2-C02ET
305 H2N-PH-2-COCH3
306*HO-PH-2-CONH2
307 H2N-PH-2-CONH2
308 PYR-2-CONH2-3-OH
109 BR-PH-2-OCONHCH3
jlO BR-PH-2-OCON(ME)2
°11 BR-PH-2-OCOCH3
12 CL-PH-2-NHCOCH3
313 CL-PH-2-OCONHCH3
"14 CL-PH-2-OCOCH3
15 CL-PH-2-OME-5-
316 CL-PH-2-C02CH3
17 CL-PH-2-COCH3
IB l,3-CL2-PH-4-M _
319 l,4-CL2-PH-2-OCONHME
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2.55
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1."
2.
2.
1.
1.
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1.
2.
2.
3.
2.
50
94
38 -
55
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26 -
18
29 -
75 -
03
63 -
35
06
02 -
52 -
.0:
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.0(
.05
.CC
.0;
.0.1
.01
.05
.03
.03
.00
,01
!l4
.06
.14
,01
.02
-.15
-.06
.10
.12
.02
-.01
-.14
-.03
.12
.03
.10
-.20
.10
-.04
.02
.12
.34
.03
.10
.13
.09
.02
.01
.11
.15
.13
.03
.03
.02
.08
-------
PAGE 7
320 I-PH-2-OCONHME 1.94 2.33 .28 .50 1 0 0 .00 .00 2 16 -.22
321 I-PH-2-OCOCH3 2.55 2.61 .28 .50 1 0 0 .00 .00 2 43 12
322 BR-PH-2-OH 2.35 2.32 .28 1.06 1 0 0 .00 .00 2.29 .06
323 F-PH-2-OH 1.68 1.60 .28 1.06 1 0 0 .00 .00 1.58 .10
324 CL-PH-2-OH 2.19 2.17 .28 1.06 1 0 0 .00 .00 2.14 .05
325 I-PH-2-OH 2.65 2.58 .28 1.06 1 0 0 .00 .00 2.55 .10
326 CH30-PH-2-OH 1.32 1.39 .17 1.06 1 0 0 .00 .50 1.27 .05
327 C02H-PH-2-CH3 2.18 2.53 .00 .35 1 0 1 .00 .00 2.08 .10
328 CO2H-PH-2-BR 2.20 2.73 .28 .35 200 .00 .00 2.23 -.03
329 C02H-PH-2-F 1.77 2.01 .28 .35 1 0 0 .00 .00 1.80 -.03
330 CO2H-PH-2-CL 1.98 2.58 .28 .35 2 0 0 .00 .00 2.08 -.10
331 C02H-PH-2-I 2.40 2.99 .28 .35 2 0 0 .00 .00 2.48 -.03
332 C02H-PH-2-OCOCH3 1.20 1.23 .32 .50 1 0 0 .17 .35 1.15 .05
333 C02H-PH-2-OCH3 1.59 1.80 .32 .50 1 0 0 .17 .35 1.72 -.13
334 C02H-PH-2-C02CH3 1.13 1.85 .51 .35 3 0 0 .32 .27 1.24 -.11
335 C02K-PH-2-C02K .79 1.61 .32 .35 400 .32 .35 .69 .10
336 C02H-PH-2-COCH3 b c .81 1.32 .51 .35 3 0 0 .32 .27 .72 .09
337 C02H-PH-2-OET-4-NH2 * .99 1.11 .37 .65 1 0 0 .00 .00 1.05 -.06
338 PYR-2-BR-3-OCON(ME)2^ 1.14 1.00 .84 .50 1 0 0 .00 .00 1.11 .03
339 PYR-2-CL-3-OCON(ME)2 1.04 .85 .84 .50 1 0 0 .00 .00 .96 .08
340 PYR-2-I-3-OCON(ME)2c 1.26 1.26 .84 .50 1 0 0 .00 .00 1.36 -.10
341 N02-PH-2-CL 2.24 2.58 .60 .00 1 0 0 .00 .00 2.27 -.03
342 N02-PH-2-NHCOCH3 1.00 .90 ..60 1.08 200 .00 .00 .93 .07
343 N02-PH-2-KHCH3 2.18 1.38 .60 1.08 000 .00 .00 1.98 .20
344 K02-PH-2-N02 1.58 1.61 .60 .00 0 0 0 .00 .00 1.60 -.02
345 NO2-PH-2-OCONHCH3 1.02 .95 .60 .50 1 0 0 .00 .00 .95 .07
346 N02-PH-2-OCON(ME)2 1.35 1.35 .60 .50 100 .00 .00 1.34 .01
347*N02-PH-2-OCOCH3 1.55 1.23 .60 .50 1 0 0 .00 .00 1.22 .33
348 K02-PH-2-OCH3 1.73 1.85 .60 .50 100 .00 .00 1.83 -.10
349 N02-PH-2-OCH2C02H .97 1.08 .60 .50 100 .00 .00 1.07 -.10
350 N02-PH-2-C02H 1.46 1.61 .60 .35 1 0 0 .00 .00 1.51 -.05
351 N02-PH-COCH3 1.28 1.32 .60 .27 1 0 0 .00 .00 1.18 .10
352 CH3-PH-2-CONHNH2 .22 .87 .32 .00 2 0 1 .00 .00 .16 .06
353 NO2-PH-2-CONHNH2 -.54 -.05 .60 .72 3 0 0 .00 .00 -.48 -.06
354 CH3O-PH-2-CONHNH2 .25 .14 .32 .50 1 0 0 .17 .72 .15 .10
355 CL-PH-2-NH2 1.90 1.61 .28 1.08 0 0 0 .00 .00 1.88 .02
356 I-PH-2-NH2 2.32 2.02 .28 1.08 0 0 0 .00 .00 2.29 .03
357 H2NS02-PH-2-CL .74 1.02 .28 .88 200 .00 .00 .68 .06
358 H2NS02-PH-2-N02 .34 .05 .60 .88 1 0 0 .00 .00 .27 .07
J59 H2NCONH-PH-2-F .88 .97 .28 1.08 1 0 0 .00 .00 .97 -.09
J60 H2NCONH-PH-2-CL , 1.27 1.54 .28 1.08 2 0 0 .00 .00 1.25 .02
361 H2NCONH-PH-3-CL-4-OCH3^C 1.37 1.52 .34 .79 1 0 0 .00 .00 1.48 -.11
62 CONH2-PH-2rBR .73 1.50 .28 .72 3 0 0 .00 .00 .83 -.10
63 CONH2-PH-2-F .64 .78 .28 .72 1 0 0 .00 .00 .69 -.05
^64 CONH2-PH-2-CONH2 -1.73 -.84 .32 .72 5 0 0 .32 .72 -1.78 .05
65 CH30-PH-2-CON(ME)2 .71 .60 .51 .50 1 0 0 .17 .27 .61 .10
.,66 CH30CO-PH-2-C02CH3 1.56 2.09 .51 .27 3 0 0 .51 .27 1.49 .07
^67 CH3CONH-PH-2-OCH3 .98 1.09 .17 1.08 1 0 0 .00 .00 .98 .00
68 CH3CO-PH-2-OCON(ME)2 .93 1.01 .51 .50 1 0 0 .17 .27 1.01 -.08
o69 F-PH-2-OCOMHCH3 1.25 1.35 .28 .50 0 0 0 .00 .00 1.48 -.23
"70 F-PH-2-OCOCH3 1.76 1.63 .28 .50 0 0 0 .00 .00 1.75 .01
71 CF3-PH-2-OCOCH3 2.59 2.37 .49 .50 0 0 0 .00 .00 2.58 .01
372 CL-PH-2-CH3-4-OCONHCH3 2.57 2.58 .28 .50 0 0 1 .00 .00 2.54 .03
73 l,2-CL2-PH-4-NHCONHC6H5 4.70 4.28 .42 1.08 0 0 0 .00 .00 4.65 .05
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PAGE 8
374 l,2-CL2-PH-4-NHCON(ME)2
375 l,2-CL2-PH-4-OCONHCH3c
376 l/3-CL2-PH-5-NHCON(HE)2
377 l,3-CL2-PH-5-OCONHCH3c
378 NC-PH-2-OCONHCH3
379 NC-PH-2-OCOCH3
380 KO-PH-2-CN
381 HO-PH-2-CF3
3 82 *PYR-2-OCH3 -4-CONHNH2f2'c
383*PYR-2-OET-4-CONHNH2 G'c
384 PYR-4-CO-PH-4-CH3
385 PYR-4-CO-PH-4-CLe
3 86 PYR-4-CO-PH-4-N02 c
387 PYR-4-CO-PH-4-OCH3Z>'c
388 PYR-4-CO-PH-4-OHZ>'c
389 PYR-4-CO-PK-4-SO2NH2 fc*e
390 CHO-PH-2-CH3-4-OCH3
391 N02-PH-2-OH
392 N02-PH-2-CHO
393 N02-PH-3-CH2C02H
394 N02-PH-4-CH20H
395 N02-PH-4-CH2C02H
396 FS02-PH-4-CH2CO2H
397 CH3S02-PH-3-CH2C02H
398 KO2-PH-4-NHS02PH-4-KH2
399 N02-PH-2-CF3-4-S02NH2c
400 l,2-CL2-PH-4-NHCONH2e
401 N02-PH-3-CH20H
a. rho values added
i>- rho values averaged
c. multiple sisma values factored
* outliers NOT included in some regression equations; see Discussion.
t Additive Log P; see METHODS section for definition of this and other parameters.
tt Observed Log P; see Ref. 16 in text.
2.79
2.80
3.07
3.03
.86
1.33
1.60
2.80
-.10
.48
2.51
2.61
1.76
1.94
1.37
.55
2.23
1.79
1.74
1.45
1.26
1.37
1.86
.06
2.14
1.73
2.64
1.21
2.40
2.63
2.40
2.63
.64
.92
.89
2.34
-1.32
-.78
2.36
2.41
1.46
1.68
1.03
-.12
2.07
1.20
1.22
1.15
.84
1.15
1.49
-.22
1.09
.93
2.25
.84
.42
.42
.42
.42
.65
.65
.65
.48
.80
.80
.84
.98
1.17
.91
1.01
1.11
.58
.60
.60
.60
.60
.60
.71
.65
.60
.81
.42
.60
1.03
.50
1.08
.50
.50
.50
1.06
1.06
1.22
1.22
.27
.27
.27
.38
.66
.57
.50
1.06
.44
.21
.67
.21
.21
.21
1.08
.88
1.08
.67
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
0
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0
1
0
0
0
0
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0
0
0
0
0
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80
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53
79
38
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41
63
75
99
65
49
26
79
46
27
22
27
62
07
25
59
65
22
-.0.1
.00
.27
.23
-.09
.11
.07
.01
.28
.33
.10
-.02
.01
-.05
-.28
.07
-.03
.00
.28
.18
.04
.10
.24
.13
-.11
.14
-.01
-.01
------- |