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.
E
S
A
B
V
0.664
0.752
0.601
0.636
0.495
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.

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.

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
A summary of all current results for the solubility of this compound in order of increasing solubility.
3-phenyl-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 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.

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
A summary of all current results for the solubility of this compound in order of increasing solubility.

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.

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
A summary of current results from model001 of this compound in order of increasing solubility.

Conclusion

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

References

[Abraham09] Abraham MH, et al. 2009. Prediction of Solubility of Drugs and Other Compounds in Organic Solvents. Journal of Pharmaceutical Sciences. DOI: 10.1002/jps.21922
[Platts99] Platts JA; Butina D; Abraham MH; and Hersey A. Estimation of Molecular Linear Free Energy Relation Descriptors Using a Group Contribution Approach. J. Chem. Inf. Comput. Sci. 1999, 39, 835-845
[Wang07] Wang, S; Li, Q-S; and Su, M-G. Solubility of 1H-1,2,4-Triazole in Ethanol, 1-Propanol, 2-Propanol, 1,2-Propanediol, Ethyl Formate, Methyl Acetate, Ethyl Acetate, and Butyl Acetate at (283 to 363) K. J. Chem. Eng. Data, 2007, 52 (3), pp 856–858
[Viasov88] Viasov, ON and Sukhova, SI. Thermodynamic properties of Solutions of 1,2,4-triazole in Water and Certain Organic Solvents. Russian Journal of Physical Chemistry, 1988, 62 (7), pp 1916-1918