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Petr Beňovský
SOLVENT SELECTION

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IMPORTANCE OF SOLVENTS
•Reaction medium (transport, combine, separate)
•Dissolution
•(In)solubility
•Kinetics
•Health
•Safety
•Environmental aspects
•Course of the reaction
•Cost (purchase, recycle, dispose)
•

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PERSPECTIVE ON SOLVENT SELECTION
ASPECT
COMMENT
Safety
Avoid solvents that are toxic or highly flammable
Promote high-yielding reactions
Compatible with desired chemistry; Can isolate product in good yield?
Convenient (minimize processing operations)
Isolate product from reaction solvent?
Operate at high concentrations?
Water miscibility
Azeotroping ability
Control amount of water
Cost of bulk and recoverability
More important at end of development cycle
Environmental
Ethics, and cost of recovery and non-compliance
Long-term availability
Acceptability for human use
Water as solvent
But, recovery of product from aqueous layer can be costly, plus cost of disposal
Neat reactions
Ionic liquids

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SOLVENT SELECTION GUIDES
Almost every company created specific solvent guide
SmithKline Beecham – Curzons, A.D. et al Clean Products and Processes 1, 82 (1999)

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SOLVENT SELECTION GUIDES
Sanofi – Prat D. et al Org.Process Res. Dev. 17, 1517 (2013)

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SOLVENT SELECTION GUIDES
GlaxoSmithKline – Henderson, R.K. et al Green Chemistry 13, 854 (2011)

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SOLVENT SELECTION GUIDES
ACS Green Chemistry Institute® Roundtable Solvent Selection Guide, March 2011

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SOLVENT CONSIDERATIONS
Watch out hydrocarbon solvents with even number of carbons (toxicity, electrostatic buildup);
Classification of solvents – ICH Harmonised Guideline Q3C – Impurities: Guideline for Residual
Solvents
Class 1 – solvents to be avoided (known human carcinogens, strongly suspected human carcinogens,
and/or environmental hazards, e.g. carbon tetrachloride (concentration limit 4 ppm),
1,2-dichloroethane (5 ppm), 1,1,1-trichloroethane (1500 ppm), benzene (2 ppm))
Class 2 – solvents to be limited (non-genotoxic animal carcinogens, agents of irreversible
toxicity, e.g. acetonitrile (410 ppm), chlorobenzene (360 ppm), chloroform (60 ppm),
N,N-dimethylformamide (880 ppm), hexane (290 ppm), methanol (3000 ppm), N-methylpyrrolidone (530
ppm), toluene (890 ppm))
Class 3   –  solvents with low toxic potential (permissible daily  exposure 50 mg or more per day,
e.g. acetic acid, acetone, ethyl acetate, heptane, 2-propanol, triethylamine)
Solvents for which no adequate toxicological data was found – a manufacturer is asked to supply
justification for residual levels of these solvents (e.g. diisopropyl ether, petroleum ether,
trifluoroacetic acid)

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SOLVENT CONSIDERATIONS
The best reaction solvent is the one that crystallizes the product directly from the reaction;
Novartis – the Dimroth rearrangement – temperature and solubility turned out to be the most
important – the product simply precipitated from the reaction mixture;
Fischer, R.W. Org.Process Res. Dev.5, 581 (2001)

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SOLVENT CONSIDERATIONS
Dyson, P.J.; Jessop, P.G. Catal.Sci.Technol.6, 3302 (2016)

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SOLVENT CONSIDERATIONS
Homogeneous vs. Heterogeneous
Reactions using gases
Insolubility is sometimes advantageous (the Schotten-Baumann reaction, the Finkelstein reaction)
Menshutkin (1890)
The reaction rate of the reaction rate of triethylamine with alkyl halides providing quaternary
ammonium salts strongly depends on a solvent (hexane 1, acetone 338, benzyl alcohol 739)
Solvents commonly used in academia are not often welcomed for industrial applications
Safety first !

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SOLVENT CONSIDERATIONS
The Finkelstein reaction
The reaction driven to completion by exploiting the different solubility of used and formed halides

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SOLVENT CONSIDERATIONS
The Halex reaction

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MIXING OF HETEROGENEOUS MIXTURES
Anderson, N.G. Practical Process Research and Development, A guide for organic chemists, 2nd
Edition, Elsevier 2000

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SOLVENT CONSIDERATIONS
Solvent
TWA (ppm)
Acetone
500
EtOAc
400
MeOH
200
t-BuOH
100
MTBE
50
MeCN
20
DMF
10
Pyridine
1
2-Methoxyethanol
0.1
TWA = Time-Weighted Average  shift for five days for nearly for safe exposure over an 8 h shift for
five days for nearly all workers

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SOLVENT CONSIDERATIONS
Also, always consider physical-chemical properties like
•Flash point
•Flammability
•Boiling point
•Melting point
•Electrostatic charge accumulation
•Recycling potential
•Cost of solvent
•Environmental aspects
•Cost of disposal
•Polarity

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SOLVENT CONSIDERATIONS
Solvents rarely used in the pharmaceutical industry
Solvent
Disadvantage
Alternative replacement
Diethylether
Flammable
MTBE
Diisopropylether
Peroxide formation
MTBE
Hexane
Electrostatic charge
Neurological toxicity
Heptanes, i-octane
Chloroform
Mutagenicity, environmental aspects, toxicity
Dichloromethane,
2-MeTHF, toluene
Benzene
Toxicity
Toluene
Ethylene glycol
Toxicity
1,2-Propandiol
Acetonitrile
Animal teratogen, potential acetamide generation (genotoxic)
2-propanol,
acetone - water

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SOLVENT CONSIDERATIONS
Solvents preferred for process development (Pfizer)
Preferred
Usable
Undesirable
Water
Cyclohexane
Pentane
Acetone
Heptane
Hexanes
Ethanol
Toluene
Diisopropyl ether
2-Propanol
Methyl cyclohexane
Diethyl ether
Ethyl acetate
MTBE
Dichloroethane
i-Propyl acetate
i-Octane
Dichloromethane
Methanol
2-MeTHF
Chloroform
Methyl ethyl ketone
DMSO
DMF
n-Butanol
AcOH
NMP
t-Butanol
Ethylene glycol
1,4-Dioxane
Benzene
Carbon tetrachloride

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SOLVENT CONSIDERATIONS
Polarity of solvents
Hughes-Ingold rules ((de)stabilization of transition state)
Aliphatic nucleophilic substitution and elimination reactions;
Considering pure electrostatic interactions between ions or dipolar molecules amd solvent molecules
in initial and transition states;

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SOLVENT CONSIDERATIONS
Hughes-Ingold rules

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SOLVENT CONSIDERATIONS
Hughes-Ingold rules
•An increase in solvent polarity results in an increase in the rates of those reactions in which
the charge density is greater in the activated complex than in the initial reactant molecules;
•
•An increase in solvent polarity results in a decrease in the rates of those reactions in which the
charge density is lower than in the initial reactant molecules;
•
•A change in solvent polarity will have negligible effect on the rates of those reactions that
involve little or no change in the charge density from reactants to the activated complex.

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SOLVENT CONSIDERATIONS
Polarity of solvents
Reichardt, C. Pure Appl.Chem 76, 1903 (2004)
Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
3 rd Ed., Wiley-VCH, 2003

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SOLVENT CONSIDERATIONS
Polarity of solvents
ETN parameter – the negative solvatochromism of the p ® p* shifts of solutions of the betaine dye –
more polar solvents stabilize the ground energy of the polar dye, producing thus greater shift in
the position of p ® p* absorption relative to that found for solutions of the dye in
tetramethylsilane.
Colors of this dye in a solvent are indicative of the polarities of the solvent and solvent
combination used to dissolve it.

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SOLVENT CONSIDERATIONS
Polarity of solvent
Solvent
Polarity
ETN
Solubility in water (wt%)
Bp of water-solvent azeotrope
wt% of water removed by azeotrope
ICH solvent class
Water
1.000
-
None
None
EtOH
0.654
¥
78 °C
4.0
3
AcOH
0.648
¥
77 °C
97
3
DMF
0.404
¥
None
None
2
Acetone
0.355
¥
None
None
3
CH2Cl2
0.309
1.3
38 °C
1.5
2
Toluene
0.099
0.06
84 °C
13.5
2
Et3N
0.043
5.5
75 °C
10
3
Heptane(s)
0.012
0.0004
79 °C
12.9
3
Cyclohexane
0.006
0.006
69 °C
9
2

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SOLVENT CONSIDERATIONS
Polarity of solvent mixtures
Solvent
Polarity
ETN
Solvent mixture
Calculated
ETN
MeOH
0.762
EtOH:H2O = 6.9:3.1
0.762
EtOH
0.654
Acetone:H2O = 4.6:5.4
0.654
H2O:CH2Cl2 = 0.2:99.8
0.310
H2O:MIBK = 1.9:98.1
0.283
H2O:CH2Cl2 = 0.2:99.8
0.310
H2O:EtOAc = 3.3:96.7
0.253
H2O:CH2Cl2 = 0.2:99.8
0.310
H2O:2-MeTHF = 5.3:94.7
0.223
i-PrOAc
0.210
Heptanes:EtOAc = 0.8:9.2
0.210
MeOH:H2O = 7:1
0.792
EtOH:H2O = 5:3
0.783

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SOLVENT CONSIDERATIONS
Tendency of solvents to form azeotropes with water is considered advantageous (it is not practical
and economical to dry solvents using drying agents on large scale);
Be careful – dependence on pressure (breaking the azeotrope)
Pressure (mm)
Bp (°C)
Water in azeotrope (wt%)
760
70.4
8.5
250
42.6
6.3
25
1.9
3.6
Effect of reducing distillation pressure on EtOAc – water:

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IMPURITIES IN SOLVENTS
Absolute solvents are rather expensive, common solvents contains some amount of water, for certain
operations they should be dried (azeotropic distillation, molecular sieves, use of an excess of
cheap reagent);
Denatured solvents (ethanol)
Stabilizers (e.g. BHT in THF)
Tendency to form (hydrogen)peroxides (diisopropyl ether, butadiene, acetaldehyde, 1,4-dioxane,
styrene, acrylonitrile, 2-butanol, benzyl alcohol, THF, MIBK, 2-propyl alcohol)

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IMPURITIES IN SOLVENTS
Degradation of solvents (ethyl acetate, DMF)
Side reactions (reesterifications, reaction with dichloromethane)
Avoid unwanted formation of esters of sulfonic acids (potentially mutagenic)

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SACRIFICIAL SOLVENTS
Harrington, P.J. et al Org. Process Res. Dev. 10, 1157 (2006)
About 50 eq. of 98% H2SO4 at 50 oC for 3 h followed by an aqueous quench provided ring sulfonation
in the product;
5-6 eq. of 98% H2SO4 in toluene at 70 oC for 2 h – sulfonation of the product was significantly
diminished.

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IONIC LIQUIDS
Ionic liquids are ionic compounds (salts) which are liquids below 100 oC. More commonly, ionic
liquids have melting points below room temperature.

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IONIC LIQUIDS


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SUPERCRITICAL FLUIDS
Jessop, P.G.; Leitner, W. Chemical Synthesis Using Supercritical Fluids, Wiley-VCH 1999

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SUPERCRITICAL CARBON DIOXIDE
Peach, J.; Eastoe, J. Beilstein J.Org.Chem. 10, 1878 (2014)
Beckman, E.J. J.Supercritical Fluids 28, 121 (2004)

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SUPERCRITICAL CARBON DIOXIDE
FOOD INDUSTRY
Coffee decaffeination
Tea decaffeination
Fatty acids from spent barely
Vitamin E, hops, spices extraction
Nicotine extraction
Natural insecticide/pesticide extraction

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SUPERCRITICAL CARBON DIOXIDE
Thomas Swan & Co., Ltd.
Licence, P. et al  Green Chem. 5, 99 (2003)