Quantitative structure-property relationship: XXVI. Toxicity of aliphatic carboxylic acids

40

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 1, pp. 40 � 44. � Pleiades Publishing, Inc., 2006.Original Russian Text � I.B. Golovanov, S.M. Zhenodarova, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 1, pp. 44 �48.

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Quantitative Structure�Property Relationship:XXVI.1 Toxicity of Aliphatic Carboxylic Acids

I. B. Golovanov and S. M. Zhenodarova

Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences,ul. Institutskaya 3, Pushchino, Moscow oblast, 142290 Russia

Received January 13, 2005

Abstract�The previously suggested quantitative structure�property relationship was used for predictingproperties of aliphatic carboxylic acids. The boiling points, octanol�water partition factors (log P), andtoxicities [log (1/IGC50)] were calculated for a series of monocarboxylic, dicarboxylic, and unsaturatedmonocarboxylic acids. The calculated values are well consistent with the experimental data.DOI: 10.1134/S1070363206010099

Aliphatic carboxylic acids and their derivativesform a large class of organic compounds. They occu-py a prominent place in industry (petrochemistry,polymer chemistry, pharmacology, food industry, pro-duction of detergents, herbicides, insecticides, etc.),widely occur in the nature (components of fats, essen-tial oils, waxes, resins), and are intensely produced byliving bodies in the course of metabolism. Therefore,estimation of their properties, and primarily toxicity,in relation to the molecular structure is of doubtlessinterest, the more so as in a few papers on this subject([2, 3] and references therein) the �structure� is de-scribed by a set of molecular descriptors such as dis-tribution factor between an organic phase and water,LUMO energy, electrotopological state of the carboxygroup, refractive index, etc., for which there are nosimple correlations with the molecular structure;therefore, the correlations obtained do not allow esti-mation of properties upon variation of the structureand prediction of the structure of a molecule with adefinite toxicity.

Here we show that properties of aliphatic carboxyl-ic acids, including toxicity, can be estimated using thestructure�property relationship that we suggested pre-viously [4], in which a property is represented as asum of contributions corresponding to separate molec-ular fragments.

The toxicity of aliphatic carboxylic acids is deter-mined by interaction of their molecules with the envi-ronment in a living body; therefore, it is appropriateto consider the toxicity using the same approach aswith other properties determined by intermolecularinteractions. Unfortunately, systematic experimental

��1 For communication XXV, see [1].

data are available only on the boiling points of ali-phatic monocarboxylic acids. A correlation betweenthe toxicity of various organic compounds and theirpartition factor octanol�water (logP) was noted innumerous papers (see, e.g., [5�7] and referencestherein). This correlation is observed with aliphaticcarboxylic acids also [2, 3], but reliable experimentalvalues of logP are available for four compounds only[8], and the logP values given in [2, 3] were obtainedusing simple approximations with large errors. Inparticular, data given in [2] do not follow the com-monly observed trend that in compounds R�X, whereR is a hydrocarbon radical and X is a functional group(NH2, OH) or phenyl substituent, logP is the highestwith linear R, decreases in going to isomers of isostructure, and is the lowest with tertiary R [8].

Let us consider data on the boiling points, logP,and toxicity of aliphatic monocarboxylic acids. Theuse of experimental boiling points is important be-cause they are measured with a high accuracy, and thereproduction of these data demonstrates the potentialof one or another approach. Furthermore, the relation-ship between the boiling point and structure of R iswell substantiated theoretically. As the boiling point,logP, and toxicity are determined by intermolecularinteractions, they should show similar trends in varia-tion. Therefore, comparison of the available toxicitydata with the data on boiling points may be a certainreliability criterion and may be useful for constructingquantitative structure�property relationships.

To estimate the boiling point and toxicity of ali-phatic monocarboxylic acids, we used the approachdescribed in [9], according to which any collectiveproperty of molecules can be represented in the form

RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 1 2006

QUANTITATIVE STRUCTURE�PROPERTY RELATIONSHIP: XXVI. 41

Pnonlin = Plin(n) + �,

where Plin(n) is the property of a linear fragment ofthe molecule; n, number of fragments in the linearpart of R; and �, correction for branching. In accord-ance with [9, 10], we obtained the following relation-ships:

Plin(n) = k1 + k2��

n + k3��

n,

� = n�* + m�* + m�� + l�*14 + l��14 + ...,

where �* is the sum of one-fragment contributions �and two-fragment contributions � corresponding to1��2 interactions; �*, two-fragment contribution of the1��3 type corresponding to CCX interactions; �, two-fragment contribution of the 1��3 type correspondingto the CCC interactions, etc.; n, m, and m� are thenumbers of the corresponding contributions. In so do-ing, we neglected interactions more remote than 1��5.

In this approximation, the expressions for a proper-ty of valeric (1), isovaleric (2), and pivalic (3) acidswill be as follows:

1

2

P = Plin(4)

P = Plin(3) + �* + 2� + �*14

��

�14*

3 P = Plin(2) + 2�* + 3� + 2�*

�

��

�*

�*

The results of estimation of the boiling point andtoxicity of a series of aliphatic monocarboxylic acids,obtained using this approach, are given in Table 1.The contributions �, �*, and 15 appeared to be insig-nificant in estimation of the boiling point and toxicity;in the latter case, �* and 14 appeared to be also insig-nificant. Therefore, these parameters were not takeninto account in the final calculation. As seen fromTable 1, the experimental boiling points and toxicitydata are reproduced with a good accuracy.

Intermolecular interactions in branched moleculesare weaker than in linear molecules, and the extent oftheir weakening is the greater, the larger the numberof branching sites, because of shielding of the branch-ing center and the effect of �hot ends� [12]. Therefore,the boiling points of linear molecules are higher thanthose of their branched isomers, and this trend is wellreproduced in the calculations. Since the toxicity is

Table 1. Boiling points and toxicity of aliphatic carboxylicacids��

Acid

� bp, K � log (1/IGC50) a

�� experi- �

calcu-� experi- �

calcu-� ment �

lation b� ment �lation c

� [11] � � [2] ��Acetic � 391.1 � 391.2 � � � �Propionic � 414.1 � 415.1 � �0.51 ��0.38Butyric � 437.1 � 437.9 � �0.57 ��0.49Isobutyric � 427.1 � 426.1 � �0.33 ��0.38Valeric � 461.1 � 458.7 � �0.27 ��0.41Isovaleric � 449.8 � 450.7 � �0.34 ��0.27Pivalic � 437.1 � 437.1 � �0.25 ��0.37Hexanoic � 478.1 � 477.7 � �0.21 ��0.253-Methylvaleric � 470.1 � 469.4 � �0.23 ��0.184-Methylvaleric � 473.6 � 474.1 � �0.27 ��0.252-Ethylvaleric � 465.1 � 464.0 � �0.15 ��0.11Heptanoic � 496.6 � 495.3 � �0.11 ��0.06Octanoic � 510.1 � 511.8 � 0.08 � 0.152-Ethylhexanoic � 497.1 � 497.4 � 0.08 ��0.022-Propylpentanoic � 493.1 � 493.7 � 0.03 ��0.03Nonanoic � 527.1 � 527.3 � 0.35 � 0.37Decanoic � 542.1 � 542.0 � 0.51 � 0.59Undecanoic � 553.1 � 555.9 � 0.90 � 0.81Dodecanoic � 572.1 � 569.4 � � � �r � �0.9997 � �0.9753s � �1.5354 � �0.0958��a The toxicity is evaluated by the quantity log (1/IGC50), where

IGC50 is the concentration of a toxic substance at which thedevelopment of living bodies (Tetrahymena pyriformis in thegiven case [2]) is 50% suppressed. b The following parameterswere used in the calculations: k1 252.3369�7.3648, k291.2529�1.8445, k3 47.6355�6.5443, �* 11.0370�0.7931,�14 �2.0823�1.1070, �*14 1.7703�1.4596, and �*15 6.4388�1.6499. c The following parameters were used in the calcula-tion: k1 �7.0922�0.9060, k2 1.9353�0.2130, k3 5.6237�0.8946, �*14 0.2265�0.0609, and �*15 0.1566�0.0681.

also determined by intermolecular interactions, it canbe anticipated that it will vary with the molecularstructure similarly to the boiling point: Branched mol-ecules should be less toxic than their linear isomers.Experimental data on the toxicity of monocarboxylicacids given in [2] fit in this scheme only partially: forexample, in going from butyric to isobutyric acid,log (1/IGC50) increases, whereas in going from valericto isovaleric acid it decreases. There are no grounds tobelieve that carboxylic acids interact with certainreceptor centers; therefore, apparently, such inconsis-tencies are caused by significant experimental errors.Since these errors are not given, we reproduce the


42 GOLOVANOV, ZHENODAROVA

available experimental data taking into account thattheir quality is not very high.

It was noted previously [13] that butyric acid andhigher homologs can form a pseudocyclic conforma-tion:

C3

��H

�C1��C��O

OH��

��*14C2

In such structures, the C3 fragment closely ap-proaches the carbonyl oxygen atom and weakens itsinteraction with the environment. This should result indecrease the boiling point; therefore, the param-eter *14 should be minimal among all the contribu-tions *ik corresponding to the interaction of fragmentsof R with the COOH group. Shielding of the oxygenatom of the carboxy group makes the molecule morehydrophobic, and since the hydrophobicity correlateswith the toxicity, increased hydrophobicity should re-sult in increased toxicity. This means that, in toxicityestimations, the contribution *14 should be maximalamong the contributions *ik, which is the case.

Since the toxicity is often estimated from logP,within the framework of the approach described in[10] we calculated logP for a series of aliphatic mono-carboxylic acids using as the basis the data availablefor the �parent� molecule, CH3COOH. For example,for propionic (1), butyric (2), and isobutyric (3) acids,the expressions for logP in this approximation will beas follows:

1�

�

�PC2H5�COOH =PCH3�COOH + � + � + �

� �

�14

2PC3H7�COOH =PCH3�COOH + 2� + 2� + 2� + �14

3 �

�

�

Pi-C3H7�COOH =PCH3�COOH + 2� + 2� + 3�

Here � is a one-fragment contribution correspond-ing to the CH3 fragment; �, two-fragment contributioncorresponding to 1��2 interaction; �, two-fragmentcontribution corresponding to 1��3 interaction, etc.In the calculation, we used the parameters found in

[14] for the contributions to logP. The results aregiven in Table 2. The logP values obtained for ali-phatic carboxylic acids are in qualitative agreement(vary in the same direction) with those for other com-pounds R�X (X = NH2, OH, C6H5).

The coefficients of mutual correlation of the boil-ing point, logP, and toxicity of monocarboxylic acids,determined in this study, are as follows:

bp log P log (1/IGC50)

bp 1 0.963 0.928log P 1 0.963log (1/IGC50) 1

Thus, using data on logP, it is possible to estimatelog (1/IGC50) with a correlation coefficient of 0.9628,which is somewhat worse than the results given inTable 1.

We consider dicarboxylic and unsaturated carbox-ylic acids separately from monocarboxylic acids, sincemolecules of dicarboxylic or unsaturated carboxylicacids interact with each other and with the environ-ment more strongly, and many additional parametersshould be introduced when considering these acids inthe same set with monocarboxylic acids. Separateconsideration significantly simplifies the problem.

Data on the toxicity of dicarboxylic and unsatu-rated monocarboxylic acids are available only for thelinear compounds; their properties can be describedby simple functions of n (number of C atoms in R)[10]. When considering dicarboxylic acids, it is ap-propriate to single out malonic acid because of strongintramolecular H bonding, for which a correction �Hshould be made. Then, log (1/IGC50) of dicarboxylicacids, like any other property determined by intermo-leculare interactions, can be expressed as follows:P = k1 + k2n + �H, where n is the number of C atomsin R. For unsaturated carboxylic acids of the typeR�CH=CH�COOH (R�X at X = CH=CH�COOH),P = k1 + k2n.

The toxicities thus estimated are given in Tables 3and 4; it is seen that the experimental data are repro-duced with a good accuracy. The toxicity of unsatu-rated monocarboxylic acids can be estimated moreaccurately using the expression P = k1 + k2n

1.5. How-ever, we do not consider this opportunity, as faster,compared to the function n1, increase in the intermo-lecular interactions cannot be explained. The rmsdeviation obtained in the calculations is close to thepresumed error of the toxicity determination, andthere is no need in further refinements.


QUANTITATIVE STRUCTURE�PROPERTY RELATIONSHIP: XXVI. 43

Table 2. Octanol�water partition factors of aliphatic monocarboxylic acids��

Molecule

�

Expression for property

� log P� �� experiment �

this� �and calculation �

worka� � [2] �

��CH3COOH �a � �0.17b � �0.17C2H5COOH �a + � + � + � � 0.33c � 0.39C3H7COOH �a + 2� + 2� + 2� + �14 = PC2H5�COOH + � + � + � + �14 = � 0.79c � 0.90

�PC2H5�COOH + � � �i-C3H7COOH �a + 2� + 2� + 3� � 0.99 � 0.82C4H9COOH �a + 3� + 3� + 3� + 2�14 = PC3H7�COOH + � + � + � + �14 = � 1.39c � 1.41

�PC3H7�COOH + � � �i-C4H9COOH �a + 3� + 3� + 4� + 2�14 � 1.16 � 1.28t-C4H9COOH �a + 3� + 3� + 6� � 1.47 � 1.12C5H11COOH �PC4H9�COOH + � � 1.92 � 1.923-Me�C4H9COOH �PC4H9�COOH + � + � + 2� + 2�14 � 1.75 � 1.744-Me�C4H9COOH �PC4H9�COOH + � + � + 2� + �14 � 1.75 � 1.792-Et�C3H7COOH �PC3H7�COOH + 2� + 2� + 3� + 3�14 � 1.68 � 1.74C6H13COOH �PC5H11�COOH + � � 2.42 � 2.43C7H15COOH �PC5H13�COOH + � � 3.05 � 2.942-Et�C5H11COOH �PC5H11�COOH + 2� + 2� + 3� + 3�14 � 2.64 � 2.762-Pr�C4H9COOH �PC4H9�COOH + 3� + 3� + 3� + 4�14 � 2.75 � 2.89C8H17COOH �PC7H15�COOH + � � 3.47 � 3.45C9H19COOH �PC8H17�COOH + � � 4.09 � 3.96C10H21COOH �PC9H19�COOH + � � 4.42 � 4.47C11H23COOH �PC10H21�COOH + � � 4.60 � 4.98

��a In the calculation we used the parameters obtained in [14]: � 1.10, � �0.41, � �0.13, �14 �0.05; more remote contributions are

small and were neglected. b Experimental value from [8]. c The same values were obtained experimentally in [8].

Table 3. Toxicity of aliphatic dicarboxylic acids��

Acid� log (1/IGC50)��experiment [2] � this worka

��Malonic � �0.71 � �0.71� �Succinic � �0.94 � �0.84� �Glutaric � �0.64 � �0.61� �Adipic � �0.61 � �0.65� �Pimelic � �0.58 � �0.56� �Suberic � �0.51 � �0.47� �Sebacic � �0.29 � �0.28� �1,10-Decanedicarboxylic � �0.09 � �0.09� �1,12-Dodecanedicarboxylic� 0.08 � 0.09� �r � � 0.9830� �s � � 0.0656��a The following parameters were used in the calculation: k1�1.0261�0.0500, k2 0.0930�0.0071, �H 0.22.

Table 4. Toxicity of aliphatic unsaturated monocarboxylicacids��

Acid� log (1/IGC50)��experiment [2] � this worka

��Crotonic � �0.54 � �0.54trans-2-Pentenoic � �0.28 � �0.36trans-2-Heptenoic � �0.13 � �0.142-Octenoic � 0.21 � 0.292-Nonenoic � 0.60 � 0.55r � � 0.9902s � � 0.0714��a The following parameters were used in the calculation: k1�0.8181�0.0717, k2 0.0603�0.0049.

Thus, for aliphatic carboxylic acids of variousstructures, the major structural factor affecting thetoxicity is the size of the substituents; therefore, allpredictions of the toxicity for compounds of this class


44 GOLOVANOV, ZHENODAROVA

are trivial. However, the correlation of the toxicitywith logP suggests that halogenated acids, being morehydrophobic, should be more toxic.

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13. Newman, M.S., Steric Effects in Organic Chemistry,New York: Wiley, 1956. Translated under the titleProstranstvennye effekty v organicheskoi khimii,Moscow: Inostrannaya Literatura, 1960, p. 212.

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Quantitative structure-property relationship: XXVI. Toxicity of aliphatic carboxylic acids