1,2,4-triazole+derivatives

=Predicting the solubility of 1,2,4-triazole derivatives by modifying the Abraham descriptors of 1,2,4-triazole=

Researchers
Jean-Claude Bradley and Andrew Lang

Objective
To predict the solubility of 3,5 disubstituted 1,2,4-triazole. The first targets include: 3-tert-butyl-5-methyl-1,2,4​-triazole SMILES: CC(C)(C)c1nc(C)nn1 CSID: 18990779

3-phenyl-5-methyl-1,2,4-triazole SMILES: n1c(nnc1C)c2ccccc2 CSID: 516702

3,5-diisopropyl-1,2,4-triazole SMILES: CC(C)c1nc(nn1)C(C)C CSID: 13496937

Background
The solubility of 1,2,4-triazole in various solvents at different temperatures is available from [Wang07 & Viasov88]. Simple linear regression can be performed on these values to determine the Abraham descriptors for 1,2,4-triazole which in turn can be used to predict the solubility of 1,2,4-triazole in over 70 solvents [Abraham09] - see also the entry in the live data book. Then instead of predicting the Abraham descriptors of the 3,5 disubstituted 1,2,4-triazole compounds ab initio, either directly from their chemical structure (SMILES) using model001 or by the additive group contribution method of Platts et. el. [Platts99], we can use the Abraham descriptors found for 1,2,4-triazole as base values and modify them by adding the Platts' values of the substituents to the base descriptors. A direct comparison of both predictive models and experimental values is available [|here].

Abraham descriptors of 1,2,4-triazole
The Abraham descriptors S,A, and B of 1,2,4-triazole were calculated by regressing measured solubility values against Abraham's general solvation equations [Abraham09]. The Abraham descriptors E and V were calculated from structure. See the benzoic acid example for a more in-depth overview of these methods. Using the methods just described, we derived the following for the Abraham descriptors of 1,2,4-triazole. A comparison between measured solubility of 1,2,4-triazole and predictions based on the above experimentally determined Abraham descriptors and predicted Abraham descriptors from Model001 are provided [|here].
 * E || S || A || B || V ||
 * 0.664 || 0.752 || 0.601 || 0.636 || 0.495 ||

Abraham descriptors of 1,2,4-triazole derivatives
Comparing the [Platts99] fragments of 1,2,4-triazole with its 3,5 disubstituted derivatives, we see that both the 3 and 5 positions change from type (Table2:6) =C- to type (Table2:7) =C< in all derivatives. The Abraham descriptors of all the derivative compounds should thus be modified as follows: E:+0.224, S:+0.101, A:+0.000, B:-0.022.

1,2,4​-triazole
A summary of all current results for the solubility of this compound in [|order of increasing solubility].

3-tert-butyl-5-methyl-1,2,4​-triazole
In addition to the basic changes to the 3 and 5 positions mentioned above, we see that we also need to add one >C< (Table2:8) and four -CH3 (Table2:1) groups to complete the structure of 3-tert-butyl-5-methyl-1,2,4-triazole. The Abraham descriptors should thus be modified (in addition to any previous modifications) as follows: E:-0.116, S:-0.179, A:+0.000 ,B:+0.047. By doing exactly that, we calculate the Abraham descriptors of 3-tert-butyl-5-methyl-1,2,4-triazole to be as seen in the table below. A summary of all current results for the solubility of this compound in [|order of increasing solubility]. In addition to the basic changes to the 3 and 5 positions mentioned above, we see that we also need to add six =CH- (Table2:6) and one -CH3 (Table2:1) groups to complete the structure of 3-phenyl-5-methyl-1,2,4-triazole. The Abraham descriptors should thus be modified (in addition to any previous modifications) as follows: E:+0.304, S:+0.225, A:+0.000 ,B:+0.073. By doing exactly that, we calculate the Abraham descriptors of 3-phenyl-5-methyl-1,2,4-triazole to be as seen in the table below. A summary of all current results for the solubility of this compound in order of increasing solubility.
 * || E || S || A || B || V ||
 * 1,2,4-triazole || 0.664 || 0.752 || 0.601 || 0.636 || 0.495 ||
 * modifiers || * || -0.078 || +0.000 || +0.025 || * ||
 * 3-tert-butyl-5-methyl-1,2,4-triazole || 0.653 || 0.674 || 0.601 || 0.661 || 1.200 ||
 * E and the McGowan volume V are calculated from structure. We also note the Abraham descriptors for 3-tert-butyl-5-methyl-1,2,4-triazole predicted by model001 (E:0.653, S:0.790, A:0.000, B:1.025, V:1.200). Using the values in the table, we can predict the solubility of 3-tert-butyl-5-methyl-1,2,4-triazole in over seventy solvents. 3-tert-butyl-5-methyl-1,2,4-triazole is predicted to be miscible with all primary alcohols with Abraham descriptors, THF, DMSO, DMF, and acetone; see the table below for a selected (relatively) low solubility predictions.
 * solvent || conc.(M) ||
 * carbon disulfide || 0.156 ||
 * chloroform || 3.218 ||
 * hexane || 0.083 ||
 * toluene || 0.789 ||
 * benzene || 1.026 ||
 * carbon tetrachloride || 0.366 ||
 * 3-phenyl-5-methyl-1,2,4-triazole**
 * || E || S || A || B || V ||
 * 1,2,4-triazole || 0.664 || 0.752 || 0.601 || 0.636 || 0.495 ||
 * modifiers || * || +0.326 || +0.000 || +0.051 || * ||
 * 3-phenyl-5-methyl-1,2,4-triazole || 1.245 || 1.078 || 0.601 || 0.687 || 1.244 ||
 * E and the McGowan volume V is calculated from structure. We also note the Abraham descriptors for 3-phenyl-5-methyl-1,2,4-triazole predicted by model001 (E:1.245, S:1.209, A:0.000, B:1.068, V:1.244). Using the values in the table, we can predict the solubility of 3-phenyl-5-methyl-1,2,4-triazole in over seventy solvents. 3-phenyl-5-methyl-1,2,4-triazole is predicted to be miscible with all alcohols with Abraham descriptors, THF, DMSO, DMF, and acetone; see the table below for a selected (relatively) low solubility predictions.
 * solvent || conc.(M) ||
 * carbon disulfide || 0.100 ||
 * chloroform || 1.662 ||
 * hexane || 0.022 ||
 * toluene || 0.511 ||
 * benzene || 0.693 ||
 * carbon tetrachloride || 0.160 ||

3,5-diisopropyl-1,2,4-triazole
In addition to the basic changes to the 3 and 5 positions mentioned above, we see that we also need to add two >CH- (Table2:3) and four -CH3 (Table2:1) groups to complete the structure of 3-isopropyl-5-isopropyl-1,2,4-triazole. The Abraham descriptors should thus be modified (in addition to any previous modifications) as follows: E:-0.238, S:-0.228, A:+0.000 ,B:+0.050. By doing exactly that, we calculate the Abraham descriptors of 3-isopropyl-5-isopropyl-1,2,4-triazole to be as seen in the table below. A summary of current results from model001 of this compound in [|order of increasing solubility].
 * || E || S || A || B || V ||
 * 1,2,4-triazole || 0.664 || 0.752 || 0.601 || 0.636 || 0.495 ||
 * modifiers || * || -0.127 || +0.000 || +0.028 || * ||
 * 3,5-diisopropyl-1,2,4-triazole || 0.659 || 0.625 || 0.601 || 0.664 || 1.341 ||
 * E and the McGowan volume V is calculated from structure. We also note the Abraham descriptors for 3-isopropyl-5-isopropyl-1,2,4-triazole predicted by model001 (E:0.659, S:0.799, A:0.000, B:1.051, V:1.341). Using the values in the table, we can predict the solubility of 3-isopropyl-5-isopropyl-1,2,4-triazole in over seventy solvents. 3,5-diisopropyl-1,2,4-triazole is predicted to be miscible with primary alcohols, chloroform*, THF, DMSO, DMF, and acetone; see the table below for a selected solubility predictions.
 * solvent || conc.(M) ||
 * carbon disulfide || 0.455 ||
 * chloroform || 6.481* ||
 * hexane || 0.220 ||
 * toluene || 2.001 ||
 * benzene || 2.521 ||
 * carbon tetrachloride || 1.000 ||

Conclusion
The best model available for these derivatives is likely the [|modified Platts fragment model]. Solubility measurements of the derivatives are needed for confirmation.