Solvent Selection

Methodology
Department Editor: Rita L. D'Aquino

A STEPWISE PROCEDURE TABLE 1. Some well-known databases and solvent selection tools
Databases Address and comments
Organic solvents have been used in many industries for centu-
ChemFinder Searchable data and hyperlink index: http://chemfinder.cambridgesoft.com
ries, but the methods and tools to select optimal solvents while
minimizing their adverse environmental, health, safety and op- Solvents Databases Solvent substitution data systems at http://es.epa.gov/ssds/ssds.html;
erational concerns are still evolving. The appropriate selection “Handbook of Solvents” from www.chemtec.org/cd/ct_23.html; and
of solvents depends to a large extent on the application — more SOLVDB at http://solvdb.ncms.org/index.html
specifically on what needs to be dissolved, and under what NIST Webbook Source of physical and chemical data at http://webbook.nist.gov
conditions. This article presents a four-step approach to solvent DIPPR and www.aiche.org/TechnicalSocieties/DIPPR/About/Mission.aspx; and
selection based upon Ref. 1*, where the reader will find a list of TAPP www.chempute.com/tapp.htm
additional resources on this topic. CAPEC Database Pure as well as mixture properties data, including solvent-solute database:
www.capec.kt.dtu.dk/Software/ICAS-and-its-Tools
Identify the challenge and solvent characteristics. Selection Tools Address and comments
The first two steps are: 1) identifying the actual problem and SMSwin A specialized software for property estimation and solvent classification:
technology or unit operation required to solve it; and 2) defining www.capec.kt.dtu.dk/documents/software/SMSWIN.htm
the requirements that must be met by the solvent, using criteria
NRTL-SAC and Activity coefficient method based on segment contributions. Predictive based
related to its physical and chemical properties (e.g., pure-solvent
eNRTL-SAC on a small set of solubility data. Useful for crystallization solvent selection
properties, such as normal boiling point, the Hildebrand solubility and extends to LLE and VLE: www.aspentech.com
parameter at 300 K, the Hansen solubility parameters; solvent-
solute properties, such as the solubility of the solute as a function
of the composition of the mixture; and functional constraints, such TABLE 2. Well-known solvents together with their related properties
as solute loss in solute).
Solvent Name Molecule type Group type Charge NBP NMP Sol. Par.
(K) (K)
Obtain reliable values of solvent properties and
narrow down selection. There are several alternatives for this 1-Methyl-2-pyrrolidinone Amide 1 NE/EPD 475.15 249.15 23.16
third step. For example, one can measure the required properties, Acetonitrile Nitrile 1 E/NPG 354.75 229.35 24.05
use a database of properties of chemicals (or solvents), or, use Dimethyl sulphoxide S-oxide 1 E/NPG 462.15 291.65 26.75
property models to estimate them. For solvent-selection problems Dimethyl formamide Amide 1 NE/NPG 426.15 212.75 23.95
not involving chemical reactions, the pattern of the desired Dimethylacetamide Amide 1 NE/NPG 438.15 253.15 22.35
solvent is established through analysis of the solute, application Diisopropyl ether Ether 2 NE/EPD 341.65 181.35 14.45
type, and other constraints. Dimethyl ether Ether 2 NE/EPD 248.35 131.65 15.12
Once this is established, a database of known solvents can Methyl tertbutyl ether Ether 2 NE/EPD 328.35 164.55 15.07
be used to identify the solvents that match the necessary pattern Tetrahydrofuran Ether 2 NE/EPD 338.15 164.85 18.97
(Table 1). On the other hand, when chemical reactions are Chlorobenzene Chloride 3 NE/P 632.35 404.9 19.35
involved, the approach is based on transition-state theory and m-xylene (also o-; p-) Aromatic HC 3 NE/P 412.27 225.3 18.05
requires consideration of the solvation energies of the reactants,
Toluene Aromatic HC 3 NE/P 383.95 178.25 18.32
products and transition states, and thus, knowledge of the reac-
Acetic acid Acid 4 PG 391.05 289.81 19.01
tion mechanism.
When the crucial values have been found, the solvent search Propionic acid Acid 4 E/PG 414.25 252.45 19.41
could be such that first, solvent-pure properties are used, followed Sulfuric acid Acid 4 E/PG 610 283.46 28.41
ordered
by solvent-EHS, then solvent-solute, and finally solvent-function.
Narrow down the list by removing the compounds that do not Propanol Alcohol 5 E/N 370.35 147.05 24.45
match desired properties. Ethanol Alcohol 5 E/N 351.35 159.05 26.13
A protocol derived by Britest Ltd. (www.britest.co.uk) seeks to Butanol Alcohol 5 E/N 390.81 183.85 23.35
use mechanistic principles to guide solvent selection (Figure). The Ethylene glycol Alcohol 5 E/N 470.45 260.15 33.7
objective is to follow the arrows according to the problem defini- Dichloromethane Chloride 6 NE/EPD 313.15 178.05 20.37
tion and a search criterion until an end-point is reached, thereby Heptane Alkane 7 NE/I 371.65 182.55 15.2
obtaining the characteristics of the candidate solvents. These Hexane Alkane 7 NE/I 341.85 177.85 14.9
characteristics are used to identify the group to which the solvents Pentane Alkane 7 NE/I 309.22 143.42 14.4
belong using solvents database (see Table 2). The corresponding Methanol Alcohol 4, 5 E/N 337.85 175.47 29.59
group-types are evaluated and a final selection is made. Water Aqueous 4, 5 E/N 373.15 273.15 47.81

Verify selection. The fourth step is to verify that the solvent
works as expected by performing a computational validation
by simulation. Experimental validation of a solvent candidate is
required at all stages of process development.
NE = non-electrolytic solvent; E = electrolytic solvent; P = polarizable; EPD = electron-pair
donor; I = inert; PG = protogenic (proton donor); N= neutral (donor & acceptor); NPG =
non-protogenic (proton acceptor); NBP = normal boiling point; NMP = normal melting point;
Sol. Par. = Hildebrand solubility parameter at 300 K (MPa1/2)

Stability, solubility of reactants, products

Single phase or solid-liquid Two-phase or liquid-liquid Water, immiscible solvent

(polar phase is water)

Homogeous catalysis Condensation SN1/E1 SN2/E2

by Pt group complexes
High polarity
Substrate/product hydroxyl sensitive Choose ‘polarity’
Moderate polarity based on substrate
Dipolar Aromatic and reagent
aprotic hydrocarbon Yes Consider
DPA ethers, solvation No solubility. May need
(xylene) phase-transfer catalyst
aromatics
Water, carboxylic Dipolar aprotic
Group 1 Fast, low temp, Slow, high- acids, inorganic ethers Group 3
but recovery temperature, acids, lower Water,
Group 2 difficult easy recovery alcohols Group 1 alcohols Group 6
Group 3 Group 1 Group 3 Group 4 Group 2 Group 5 Group 7

*Reference: 1. Gani, R., et al., A Modern Approach to Solvent Selection, Chem. Eng., Vol. 113, No. 3, pp. 30–43, Mar. 2006. Author E-mail: rag@kt.dtu.dk