3-mercaptopropionic acid

Dissociation constant

Link to relevant study record(s)

Reference

Endpoint:

dissociation constant

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

1. SOFTWARE
Sparc

2. MODEL (incl. version number)
n.a.

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Working SMILES String: SCCC(=O)O
pKa options:
1) Calculation temperature: 20 °C
2) Full speciation study performed:
a) N both acid and base
b) C (most likely),
c) pH range: -0.2 to 14


4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
see Any other information on results incl. tables

5. APPLICABILITY DOMAIN
see Any other information on results incl. tables

6. ADEQUACY OF THE RESULT
see Any other information on results incl. tables

Guideline:

other: REACH guidance on QSARs R.6, May/July 2008

Principles of method if other than guideline:

The SPARC chemical reactivity models for estimation ionization pKa in water.

GLP compliance:

not specified

Dissociating properties:

yes

No.:

#1

pKa:

ca. 4.27

Temp.:

20 °C

Remarks on result:

other: carboxyl group

No.:

#2

pKa:

ca. 10.44

Temp.:

20 °C

Remarks on result:

other: thiol group

Validity of the model:

1. Defined endpoint: dissociation constant pKa

2. Unambiguous algorithm: To estimate pKa in water the molecular structures are broken into functional units called the reaction center (with known chemical properties) and the perturber. The reaction center is the smallest subunit that has potential to ionize and lose a proton to solvent. The perturber is the molecular structure appended to the reaction center. The pKa of the reaction center is adjusted for the molecule in question using the mechanistic perturbation models. The pKa for a molecule is expressed in terms of the contributions of both reaction center and perturber. The computational algorithm is based on the structure query provided in a form of SMILES code.

3. Applicability domain: the SPARC chemical reactivity models have been designed and parametrized to be applicable to any chemical structure. The reaction parameters describing a given reaction center (Table 1) are the same regardless of the appended molecular structure. Also for substituent the parameters in Table 2 (Tables 1, 2 taken from S.H. Hilal et al. Prediction of Chemical Reactivity Parameters and Physical Properties of Organic Compounds from Molecular Structure Using SPARC, U.S. Environmental Protection Agency, Athens, GA. Publication No. EPA/600/R-03/030, Table 4, 3) are independent of the rest of the molecule. This structure factoring and function specification enables one to compute, for a reaction center of interest, the resultant reactivity.

Chemicals for which the applicability of SPARC is limited:

a) SPARC has not been designed to calculate pKa for substances, such as quaternary amines;

b) substances with carbon acid reaction center where the perturbations for this group are very large and the measurement standard deviation is not better than 1 unit. Examples: pKa for methane, nitro-methane, tri-nitro-methane are calculated with SPARC within ±1.3pKa units;

c) substances known to tautomerize, e.g., molecules such as methyl substituted imidazole; d) covalent hydrates, which include many multiple in-ring N compounds such as quinazoline and pteridine;

e) substances with oxy acid reaction center (where the perturbations are extremely small) in structures such as 3- or 4-S-C₆H₄-YC where Y is a side chain intervening between the benzene ring (e.g., Y=(CH₂)_x) and the reaction center, (C=CO2H). However SPARC can discriminate these effects for other reaction centers, such as NR₂.

 

Table 1.Characteristics Parameters

Reaction center	ρelc	ρres	χc	(pKa)c
CO2H	1.000	-1.118	2.60	3.75
AsO2H	0.653	-0.817	2.22	6.63
PO2H	0.489	-0.394	2.72	2.23
POSH	0.291	-0.402	2.69	1.55
PS2H	0.101	-0.802	2.63	1.96
BO2H2	0.355	-0.050	3.04	8.32
SeO3H	1.207	-0.400	2.30	4.64
SO3H	0.451	-4.104	2.09	-0.10
OH	2.706	18.44	2.49	14.3
SH	2.195	4.348	2.76	7.40
NR2	3.571	19.36	2.40	9.83
in-ring N	5.726	-11.279	2.31	2.28
=N	5.390	-4.631	2.47	5.33

 

Table 2. SPARC Substituent Characteristics Parameters

Substituent	Fs	Fq	MF	Er	ris	Χs
CO2H	2.233	0.000	0.687	0.072	0.80	3.43
CO2^-	1.639	-0.603	0.560	2.978	1.00	2.68
AsO3H^-	0.300	-0.500	0.500	0.190	1.20	2.60
AsO3^-2	0.600	-1.000	0.300	0.150	1.20	2.60
AsO2H	1.000	-2.000	0.000	0.080	0.80	2.60
PO3H^-	0.600	-0.786	0.400	0.220	1.20	3.32
PO3^-2	0.600	-2.500	0.400	0.840	1.20	2.90
BO2H2	1.078	0.000	1.010	1.484	0.80	2.40
SO3^-	6.315	-1.224	2.491	1.407	0.80	2.82
OH	1.506	0.000	-3.116	7.240	0.80	2.76
SH	2.931	0.000	-1.871	3.000	0.80	2.76
O^-	1.913	-1.566	-3.546	11.00	-0.50	3.01
S^-	1.727	-1.537	-1.437	9.368	-0.50	3.34
NR2	1.190	0.000	-4.939	17.42	0.70	2.58
NR2H^+	3.978	0.779	-2.505	21.70	0.50	3.23
CH4	-1.10	0.000	-2.065	0.129	-0.63	2.30
NO2	7.460	0.000	2.515	3.677	1.00	3.79
NO	6.714	0.000	4.127	1.691	1.00	3.80
CN	5.649	0.000	3.141	3.196	0.80	3.71
OR	2.138	0.000	-4.767	1.987	0.80	2.90
SR	2.323	0.000	-1.234	1.952	0.80	2.80
I	4.270	0.000	0.000	4.928	0.75	2.95
Br	3.756	0.000	-0.031	3.012	0.70	3.19
Cl	3.622	0.000	-0.066	1.498	0.65	3.37
F	3.164	0.000	-1.718	0.800	0.65	3.67
in-ring N	5.310	0.000	0.929	2.055	0.00	3.30
in-ring^+	1.379	3.785	6.995	8.708	0.00	3.80
SO2	6.451	0.000	2.038	4.176	0.80	3.60
=N	1.533	0.000	0.544	4.918	0.00	3.80
=^+	2.000	1.000	2.800	2.600	0.00	3.80
=O	3.195	0.000	1.584	2.281	0.00	3.60

 

The test substance 3-mercaptopropionic acid, for which prediction was done, falls into applicability domain of the SPARC chemical reactivity model for estimation ionization pKa in water. Both ionisable groups present in the molecule: carboxylic and thiol are listed as tested reaction centers. The substance does not contain any chemical structure for which SPARC has limited application (see p. a)-e)). Moreover the carboxyl group is in the group of chemicals for which SPARC calculations are the most precise (calculated values within ±0.25pKa units).

The dissociation of carboxyl group is predicted in the environmentally relevant pH (pKa=4.27). Therefore further validation of the predicted value was done. The dissociation constant of several analogue substances are present in a Table 3, where experimental and calculated (by SPARC online calculator, V4.2 release) values are given.The experimental and predicted values for carboxyl group differ only by 0.08 -0.2pKa unit, for thiol group: by 0.66pKa unit, therefore calculation performed by SPARC is considered to be reliable. The calculation of SPARC is accepted as valid.

 

Table 3.

CAS	Name	Functional group	SPARC [t=20°C]	SPARC [t=25°C]	Experimental t=25°C
503-66-2	3-hydroxypropionic acid	carboxyl	4.33	4.31	4.51^*
68-11-1	thioglycolic acid	carboxyl	3.76	3.75	3.68^*
		thiol	9.97	9.88
75-08-1	Ethanethiol	thiol	10.03	9.94	10.6^**

^*CRC Handbook of Chemistry and Physics, 86^thEd., 2005-2006

^**Serjeant, EP & Dempsey,B (1979) in SRC PhysProp database

 

4. Statistical characteristic: the ionization pKa calculator was trained on ca. 2400 compounds involving all substituents and reaction centers listed in Tables 1 and 2. The overall training set RMS deviation was 0.36pKa units. In general SPARC can calculate the pKa for simple molecules such as oxy acids and aliphatic bases and acids within ±0.25pKa units; for most other organic structures such as amines and acids within ±0.36pKa units and ±0.41pKa units for =N and in-ring N reaction centers and for complicated structures. When a molecule has more than six ionization sites the expected SPARC error is ±0.65pKa units. A summary of the statistical parameters for the SPARC ionization pKa in water is in the Table 4 (taken from Hilal, S.H., S.W. Karickhoff, and L.A. Carreira. 2003. Verification and Validation of the SPARC Model.Environmental Protection Agency,,Publication No. EPA/600/R-03/033., Table 4)

 

Table 4. Statistical Parameters of SPARC pKa Calculations

Set	Training	R^2	RMS	Test	R^2	RMS
Simple organic compounds	793	0.995	0.235	2000	0.995	0.274
Azo dyes compounds	50	0.991	0.550	273	0.990	0.630
IUPAC compounds^*	2500	0.994	0.356	4338^**	0.994	0.370

^*Observed values are from many refs.

^**Carbon acid pKas are not included

 

5. Mechanistic interpretation: SPARC chemical reactivity models apply to the chemical properties in transition that is in the conversion of the molecule to a different state or structure. For chemical properties calculated in SPARC (also pKa) the energy differences between these two states of the system are small compared to the binding energy for the reactants involved. The differences in energy are calculated with use of perturbation methods, which threat the final state as a perturbed initial state and the energy differences between these two energy states are determined by quantifying the perturbation. For pKa, the perturbation of the initial state, assumed to be the protonated form, versus the unprotonated final form is factored into the mechanistic contributions of resonance (variations in the charge transfer between the π system and suitable orbital of the substituent) and electrostatic effects (charges or electric dipoles interactions, induced electric fields: mesomeric field effects, σ induction) and other perturbations such as H-bonding, steric contributions and salvation effects.

 

Adequacy of prediction: The dissociation constants for the substance 3-mercaptopropionic acid were predicted with use of the valid model. It was confirmed that the substance falls into the applicability domain of a model; therefore the result value is reliable. The obtained values are dissociation constants calculated at conditions required for regulatory purposes with respect to the temperature (20°C), pH range (-0.2 to 14). Therefore the prediction can be used for the classification and risk assessment.

Description of key information

Dissociation constant at 20°C:
1) 4.27 (carboxyl group)
2) 10.44 (thiol group)

Additional information

Two dissociation constants of the test substance 3-mercaptopropionic acid have been determined to be: 4.27 (carboxyl group) and 10.44 (thiol group) at 20.0 °C by using SPARC online calculator , V4.2 release. The dissociation of carboxyl group is predicted in environmentally relevant pH, therefore further validation of the predicted value was done on the basis of experimental and predicted by SPARC values for three other substances: 3 -hydroxypropionic acid, thioglycolic acid and ethanethiol. SPARC prediction for that substances are reliable, therefore the calculation of SPARC of dissociation constant for 3-mercaptopropionic acid is accepted as valid.