Determination of Abraham model solute descriptors for the monomeric and dimeric forms of trans-cinnamic acid using measured solubilities from the Open Notebook Science Challenge
© Bradley et al.; licensee Springer. 2015
Received: 25 September 2014
Accepted: 12 January 2015
Published: 22 March 2015
Calculating Abraham descriptors from solubility values requires that the solute have the same form when dissolved in all solvents. However, carboxylic acids can form dimers when dissolved in non-polar solvents. For such compounds Abraham descriptors can be calculated for both the monomeric and dimeric forms by treating the polar and non-polar systems separately. We illustrate the method of how this can be done by calculating the Abraham descriptors for both the monomeric and dimeric forms of trans-cinnamic acid, the first time that descriptors for a carboxylic acid dimer have been obtained.
Abraham descriptors were calculated for the monomeric form of trans-cinnamic acid using experimental solubility measurements in polar solvents from the Open Notebook Science Challenge together with a number of water-solvent partition coefficients from the literature. Similarly, experimental solubility measurements in non-polar solvents were used to determine Abraham descriptors for the trans-cinnamic acid dimer.
Abraham descriptors were calculated for both the monomeric and dimeric forms of trans-cinnamic acid. This allows for the prediction of further solubilities of trans-cinnamic acid in both polar and non-polar solvents with an error of about 0.10 log units.
The solute descriptor V is the easiest to obtain as it can be calculated directly from structure. It is equal to the McGowan characteristic volume (cm3 per mol)/100 . V encodes sized-related solvent-solute dispersion interactions, including a measure of the solvent cavity term that will accommodate the dissolved solute.
The solute descriptor E, the excess molar refractivity, can be calculated from a refractive index at 293 K for a compound that is liquid at 293 K . For other solutes E can be predicted, either directly using Absolv, part of ACD Labs proprietary ACD/ADME Suite , or through the predicted molar refractivity, freely available for individual compounds through ChemSpider , or some other source, such as the Open Source Chemistry Development Kit . Another useful method for estimating E is through summation of structural fragments from compounds with known values of E.
The solute descriptors S, A, and B can also be predicted [7,11-13] or in limited cases determined experimentally [14,15]. However, accurate results, in general much more accurate than predicted values, are easily obtained by using regression with measured solubilities and/or partition coefficient values .
Finally, we note that the applicability of the Abraham model to the solubility of crystalline organic solutes assumes three conditions. Firstly, the solute has the same form when dissolved in any solvent, including water. That is, we assume no solvate, hydrate, or complex formation. Secondly, the secondary medium coefficient must be at or near unity. This condition generally restricts the model to solutes that are not too soluble. Thirdly, if the solute ionizes in water, the aqueous solubility, Cw, is taken to be that of the neutral form. The second restriction may not be as important as initially believed. The Abraham solvation parameter model has shown remarkable success in correlating the solubility of several very soluble crystalline solutes. For example, Equations (1) and (2) described the molar solubility of 1,4-dichloro-2-nitrobenzene in 24 organic solvents to within overall standard deviations of 0.128 and 0.119 log units, respectively . Standard deviations for aspirin dissolved in 13 alcohols, 4 ethers, and ethyl ethanoate were 0.123 and 0.138 log units . 1,4-Dichloro-2-nitrobenzene and aspirin exhibited solubilities exceeding 1 molar in several of the organic solvents studied.
The Open Notebook Science Challenge  contains a valuable collection of Open Data (CC0 1.0 License: See the creative commons website for more information about this license) solubility data that could be used to determine Abraham descriptors for a large number of compounds. We illustrate the utility of the Open Notebook Science Challenge data by determining the Abraham descriptors for both the monomeric and dimeric forms of trans-cinnamic acid. The current study represents the first time that we have calculated the solute descriptors for carboxylic acid dimers. Solute descriptors are required input parameters in order to predict solute solubilities, partition coefficients, and other chemical/biological properties for which Abraham model correlations have been developed.
The measured solubility values presented here are from the Open Notebook Science Challenge , an Open Science project to collect and measure the solubility of organic compounds in organic solvents, ran by Jean-Claude Bradley, and sponsored by the Royal Society of Chemistry, Sigma Aldrich, Submeta, and Nature. The method and materials used to determine the solubility values varied by experiment and researcher and can be found in the Open Notebook .
In addition to the measured solubility values outlined above, we collected solubility values from the literature [20-24] and partition coefficients from Bio-Loom . All values (mole fraction, mass fraction and mass ratio) were converted to molarity for ease of comparison.
Solubilities of trans-cinnamic acid
We can use this difficulty to advantage by choosing polar solvents for the determination of descriptors for cinnamic acid monomer and by choosing non-polar solvents for the determination of descriptors for cinnamic acid dimer. A few solvents were excluded altogether as they currently do not have Abraham solvent parameters: pentachloroethane, tetrachloroethane, tetrachloroethylene, and trichloroethylene.
Calculating the Abraham descriptors for cinnamic acid monomer
Values of water-solvent partition coefficients, as log P s , for trans-cinnamic acid monomer
Log P s
Diethyl ether, wet
We then have a total of 21 values of log Ps, 5 being the number of partition coefficient measurements and 16 being the number of values derived from solubility ratios, using Equation (5), with log Cw taken as −2.40 . These can be converted into 21 values of log Ks. We also have two equations for log Kw, one in terms of V (Equation 1) and one in terms of L (Equation 2), and an equation for GLC retention data  thus leading to a total of 45 equations. The unknowns are S, A, L and log Kw. The set of 45 equations were solved by regression to yield the values of the four unknowns that gave the best fit of experimental and calculated properties, exactly as described before [29,30].
Calculating the Abraham descriptors for cinnamic acid dimer
For cinnamic acid, with Emonomer = 1.14 the value of Edimer is 1.68. The unknowns are then S, A, B, L, log Kw and log Cw so that it is easily possible to obtain a solution for the 20 simultaneous equations by regression.
Results and discussion
Descriptors for monomeric and dimeric cinnamic acid, and for monomeric benzoic acid
Log K w
Observed and fitted solubilities for trans-cinnamic acid monomer in polar solvents
Log P s
Log C s
Observed and fitted solubilities for trans-cinnamic acid dimer in non-polar solvents
Log P s
Log C s
Although we refer to solvents that support formation of the dimer as ‘non-polar’ solvents, the main distinguishing factor between solvents that support the dimer and those that support the monomer is the hydrogen bond basicity of the solvent. If the solvent is a hydrogen bond base, it will form solvent-solute hydrogen bonds with the OH group and will break up the dimer into the monomeric form. Trifluoroethanol as a solvent is an extremely weak hydrogen bond base. Marcus  gives values of the Kamlet-Taft solvent hydrogen bond basicity, β, as methanol (0.66), diethyl ether (0.47), propanone (0.43) propyl acetate (0.40), acetonitrile (0.40), nitrobenzene (0.30), trichloromethane (0.10), benzene (0.10), cyclohexane (0.00) and trifluoroethanol (0.00). It seems that for saturated solutions of cinnamic acid in solvents with β > 0.35 the monomer is mainly present but when the solvent β < 0.35 the dimer is mainly present.
We have determined Abraham solute descriptors for trans-cinnamic acid using solubility values measured using Open Notebook Science supplemented with values reported in the literature and with values of partition coefficients from the literature. For compounds that are not dimerized it is quite easy to perform these calculations using just solubility data. We have determined Abraham solute descriptors for the dimer of trans-cinnamic acid using just solubilities from the Open Notebook Science Challenge supplemented with values reported in the literature. This is the first time that descriptors have been assigned to carboxylic acid dimers. The Open Notebook Science Challenge details solubilities for a number of compounds that are easier to work with than cinnamic acid, because they do not form dimers. Those wishing to calculate Abraham solute descriptors for other compounds in a similar fashion can use the solubility data in the Open Notebook Science Challenge database to do so.
- Abraham MH, Smith RE, Luchtefeld R, Boorem AJ, Luo R, Acree Jr WE. Prediction of solubility of drugs and other compounds in organic solvents. J Pharm Sci. 2010;99(3):1500–15.View ArticleGoogle Scholar
- Acree WE Jr, Grubbs LM, Abraham MH. Prediction of partition coefficients and permeability of drug molecules in biological systems with Abraham model solute descriptors derived from measured solubilities and water-to-organic solvent partition coefficients. In Toxicity and drug. 2012, INTECH Publishers, Chapter 5, p. 91-128.Google Scholar
- WE Acree, Jr, LM Grubbs, MH Abraham. Prediction of toxicity, sensory responses and biological responses with the Abraham model, toxicity and drug testing, Prof. Bill Acree (Ed.). InTech. ISBN: 978-953-51-0004-1. 2012. doi:10.5772/29972. Available fromx: http://www.intechopen.com/books/toxicity-and-drugtesting/prediction-of-toxicity-sensory-responses-and-biological-responses-with-the-abraham-model.
- Abraham MH. Scales of hydrogen bonding: their construction and application to physicochemical and biochemical processes. Chem Soc Rev. 1993;22:73–83.View ArticleGoogle Scholar
- Abraham MH, Ibrahim A, Zissimos AM. The determination of sets of solute descriptors from chromatographic measurements. J Chromatogr A. 2004;1037:29–47.View ArticleGoogle Scholar
- Abraham MH, McGowan JC. The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatograph. Chromatographia. 1987;23(4):243–6. doi:10.1007/BF02311772.View ArticleGoogle Scholar
- ACD/Absolv. The Absolv prediction module calculates Abraham solvation parameters and is the result of collaboration between ACD/Labs and Prof. MH Abraham. 2014. [http://www.acdlabs.com/products/percepta/predictors/absolv/.
- Pence HE, Williams AJ. ChemSpider: an online chemical information resource. J Chem Educ. 2010;87(11):1123–4 [http://www.chemspider.com/]View ArticleGoogle Scholar
- Steinbeck C, Han Y, Kuhn S, Horlacher O, Luttmann E, Willighagen E. The Chemistry Development Kit (CDK): an open-source Java library for chemo-and bioinformatics. J Chem Inf Comput Sci. 2003;43(2):493–500.View ArticleGoogle Scholar
- Tetko IV, Gasteiger J, Todeschini R, Mauri A, Livingstone D, Ertl P, et al. Virtual computational chemistry laboratory–design and description. J Comput Aided Mol Des. 2005;19(6):453–63.View ArticleGoogle Scholar
- Platts JA, Butina D, Abraham MH, Hersey A. Estimation of molecular linear free energy relation descriptors using a group contribution approach. J Chem Inf Comput Sci. 1999;39(5):835–45. doi:10.1021/ci980339t.View ArticleGoogle Scholar
- Jover J, Bosque R, Sales J. Determination of Abraham solute parameters from molecular structure. J Chem Inf Comput Sci. 2004;44:1098–106.View ArticleGoogle Scholar
- Sprunger LM, Proctor A, Acree Jr WE, Abraham MH. Computation methodology for determining Abraham solute descriptors from limited experimental data by combining Abraham model and Goss-modified Abraham model correlations. Phys Chem Liq. 2008;46:5.View ArticleGoogle Scholar
- Abraham MH, Abraham RJ, Byren J, Griffith L. NMR method for the determination of solute hydrogen bond acidity. J Org Chem. 2006;71(9):3389–94. doi:10.1021/jo052631n.View ArticleGoogle Scholar
- Poole CF, Atapattu SN, Poole SK, Bell AK. Determination of solute descriptors by chromatographic methods. Analytica Chimica Acta. 2009; 652 1-2. doi:10.1016/j.aca.2009.04.038.Google Scholar
- Brumfield M, Wadawadigi A, Kuprasertkul N, Mehta S, Stephens TW, Barrera M et al. Determination of Abraham model solute descriptors for three dichloronitrobenzenes from measured solubilities in organic solvents. Phys Chem Liq. 2014; accepted for publication. doi:10.1080/00319104.2014.972555.Google Scholar
- Charlton AK, Daniels CR, Acree Jr WE, Abraham MH. Solubility of crystalline nonelectrolyte solutes in organic solvents: mathematical correlation of acetylsalicylic acid solubilities with the Abraham general solvation model. J Solution Chem. 2003;32:1087–102.View ArticleGoogle Scholar
- Bradley JC. 2014. Open notebook science challenge. [http://onschallenge.wikispaces.com/]
- Bradley JC. 2014. Open notebook science challenge - list of experiments. [http://onschallenge.wikispaces.com/list+of+experiments]
- Seidell A. Solubilities of inorganic and organic compounds: a compilation of quantitative solubility data from the periodical literature. 1911. D. Van Nostrand Company. Print.Google Scholar
- Desai PG, Patel AM. Effect of polarity on the solubilities of some organic acids. J Indian Chem Soc. 1935;12:131–6.Google Scholar
- Erdmann OL. Untersuchungen Uber Den Indigo. J Fur Praktische Chemie. 1841;22.1:257–99. Print.View ArticleGoogle Scholar
- Yalkowsky SH, He Y, Jain P. Handbook of aqueous solubility data. Boca Raton, FL: CRC Press; 2010. Print.View ArticleGoogle Scholar
- Wang J, Hou T, Xu X. Aqueous solubility prediction based on weighted atom type counts and solvent accessible surface areas. J Chem Inform Model. 2009;49(3):571–81.View ArticleGoogle Scholar
- Bioloom. 2014. [http://www.biobyte.com/bb/prod/bioloom.html]
- Bradley JC, Lang ASID. 2014. Cinnamic acid data temperature conversion. Open notebook science. [https://docs.google.com/spreadsheet/ccc?key=0Au_5J1f583GgdHhkY2VHNWIzanMzYzBLN1h3WVlzcWc]
- Allen G, Watkinson JG, Webb KH. An infra-red study of the association of benzoic acid in the vapour phase and in dilute solution in non-polar solvents. Spectrochim Acta. 1966;22:807–14.View ArticleGoogle Scholar
- Schupp OE, Lewis JS. Compilation of gas chromatographic data. Philadelphia: American Society for Testing and Materials; 1967. Print.Google Scholar
- Wilson A, Tian A, Chou V, Quay AN, Acree Jr WE, Abraham MH. Experimental and predicted solubilities of 3,4-dichlorobenzoic acid in select organic solvents and in binary aqueous ethanol mixtures. Phys Chem Liq. 2013;50:324–35.View ArticleGoogle Scholar
- Abraham MH, Acree Jr WE. Descriptors for artemisinin and its derivatives; estimation of physicochemical and biochemical data. Eur Chem Bull. 2013;2:1027–37.Google Scholar
- Marcus Y. The properties of organic liquids that are relevant to their use as solvating solvents. Chem Soc Rev. 1993;22:409–16.View ArticleGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.