1. What Every Chromatographer Should Know About Solvents
Colin F. Poole
Department of Chemistry
Wayne State University
USA

2. Matter The observable universe is made up of materials in the form of
Gases Liquids Solids
For chromatography stationary phases are either solids or liquids and mobile phases gases or liquids
For liquid chromatography the mobile phase is a liquid.
Since it is responsible for transporting the sample through the column or layer it is a solvent

3. How Would You Identify a Useful Solvent for Chromatography from the Category Liquids
Available in a pure form at a reasonable cost
Reasonable shelf-life (stable)
Low viscosity (water 1 cP, propan-2-ol 2.4 cP)
Low surface tension (water 73 mN/m)
Modest vapor pressure at room temperature (50<bp<125C)
Capability to form mixtures with other liquids
Safe to use (Reactivity/Toxicity/Flammability)
Compatible with the detection system
Column chromatography: critical for on-line detection
Planar chromatography: not important for volatile solvents

4. Typical Useful Solvents
Low-mass organic compounds
C1 – C4 polar compounds
< C8 low-polarity compounds
Typically monofunctional
Mutifunctional polar compounds have unfavorable physical properties
Most known for more than a century
Are there any new solvents?

5. Room Temperature Ionic Liquids
C.F. Poole and N. Lenca, Trends Anal. Chem. 71 (2015)

6. Room Temperature Ionic Liquids
Low purity (< 95% in some cases) and not easy to purify
Many are hygroscopic
Virtual absence of vapor pressure
Favorable for GC but not for other solvent applications
High viscosity (generally > 10 cP)
Roughly 1-3 orders of magnitude higher than conventional solvents
Requires dilution with a low viscosity solvent to enter the useful working range for chromatography
Slow mass transfer causes zone broadening
Surface tension (generally > 30 mN/m)
May act as reactants as well as solvents
Applications for liquid-phase microextraction most promising
N. Lenca and C.F. Poole, J. Planar Chromatogr. 30 (2017)

7. Current Situation
It is unlikely that new solvents suitable for chromatographic applications will appear in the forseeable future
Fewer than 50 solvents commonly used today
Their physicochemical properties (viscosity, surface tension, miscibility, etc.) are well known
We need a better understanding of their solvation properties to make a more informed choice for selection in chromatography

8. Polarity – A False Start
Easily understood but of limited value due to the lack of a universal definition
Solvent’s capability to enter into all possible intermolecular interactions
Solvent’s capability to enter into dipole-type interactions
No single reference compound or bulk physical property that is “uniquely polar” renders polarity scales unfit for purpose
Each scale measures some specific characteristic of the selected probe or bulk property
Individual polarity scales show little in common although supposedly describing the same general property

9. Solvent Strength and Selectivity
Single parameter estimate of a solvent’s capability to cause migration in a chromatographic system
Depends on the identity of the stationary phase
Determined by experiment
A system and a solvent property
Solvent selectivity
Multiparameter estimate of a solvent’s capability to participate in individual intermolecular interactions
Solvents can have similar strength and different selectivity
Controls band spacing

10. Solvent Strength Parameter 
Solvent strength of a pure solvent can be defined by  for inorganic oxide adsorbents
Definition
Free energy of adsorption of the solvent per unit surface area with pentane assigned as the zero reference
Organization of solvents
Ascending order of  is known as an eluotropic series
The idea of an eluotropic series is not relevant for chemically bonded stationary phases

11. Eluotropic series for silica gel
Solvent  Solvent 
n-Heptane Formamide 0.55
Toluene Propan-1-ol 0.60
Chloroform Trifluoroethanol 0.62
Methyl t-butyl ether Methanol 0.70
Dichloromethane Water
Dimethylformamide 0.51
Acetonitrile
Acetone each CH2 = -0.05

12. Solvent Strength Scale For Reversed-Phase Chromatography
Solvent Si Water 0 Solvent mixtures Acetonitrile 3.1 ST = i (Sii) Methanol 3.0 i = solvent volume fraction Acetone 3.4 Dioxane 3.5 Ethanol 3.6 Propan-2-ol 4.2 Tetrahydrofuran 4.4

13. Solvent selectivity Transfer of a compound to a solvent
Cavity Formation
Reorganization
Solute-Solvent
Interactions
Dispersion
Dipole-type
Hydrogen bond

14. Solvent Selectivity Scales
Solubility parameter model
Only contemporary use is in polymer science
No general agreement on how to calculate partial polar solubility parameters
Solvent Selectivity Triangle
Each intermolecular interaction associated with a single prototypical solute
Solvatochromic parameters
Based on spectroscopic (non-equilibrium properties)
Considers only polar interactions and not the cohesive energy of solvents
Solvation parameter model

15. Solvent selectivity triangle
A.R. Johnson, M.F. Vitha, J. Chromatogr. A 1218 (2011)

16. All solutes that are hydrogen bonding are simultaneously dipolar
Prototypical Solutes
Polar solutes with a single dominant intermolecular interaction are virtually unknown
All solutes that are hydrogen bonding are simultaneously dipolar
Ethanol Nitromethane Dioxane
s = 0.42 s = s = 0.75
a = 0.37 a = a = 0
b = 0.38 b = b = 0.64

17. Solvatochromic Selectivity Triangle

18. Solvation Parameter Model
log SP = c + eE + sS + aA + bB + lL
System Constant
Solute Descriptor
Free Energy Contribution l L
Ease of cavity formation
Dispersion interactions e E
Electron lone pair interactions s S
Dipole-type interactions a A
Solvent hydrogen bond base-solute hydrogen-bond acid interactions b B
Solvent hydrogen bond acid-solute
hydrogen bond base interactions
Mention where the lL should be.
C.F. Poole, T.C. Ariyasena and N. Lenca, J. Chromatogr. A 1317 (2013)

19. Solute descriptors V is McGowan’s Characteristic Volume
E is the excess molar refraction
S is the solute dipolarity/polarizability
A is the effective solute hydrogen-bond acidity
B is the effective solute hydrogen-bond basicity
L is the gas-liquid partition coefficient at 25C with hexadecane as a solvent
C.F. Poole, S.N. Atapattu, S.K. Poole, A.K. Bell, Anal. Chim. Acta 652 (2009)

20. Solvent Properties Solvent System constants N-Heptane -0.16 0 0 0 0.98
e s a b l
N-Heptane
Chloroform
Acetone
Methanol
Trifluoroethanol
Water

21. Solvent Properties
Transfer of solutes from the gas phase to a solvent is defined by 5 system constants
The system constants are independent of solute identity
System constants are calculated from the experimental properties of a number of varied compounds
Model suitability established by statistical parameters
Visual classification of solvents requires a reduction in data dimensionality
Principal component analysis (PCA)
Hierarchical cluster analysis (CA)

22. Chloroalkanes Alkanes Aromatic Hydrocarbonds Ethers Ketones Esters
Alcohols
Water

23. Group 2
2 a
2 b

24. Group 5 Esters, Ethers and Ketones
e s a b l

25. Group 4 Alcohols e s a b l Methanol -0.338 1.317 3.826 1.396 0.773
Propan-1-ol
Octan-1-ol

26. Select Solvents from Cluster Analysis
Solvent Cluster Classification
n-Heptane 1 Apolar
Toluene 2 Apolar aromatic
Dichloromethane 3 Haloalkane
Chloroform
Acetonitrile 4 Dipolar and weakly aprotic
Methanol 5 Amphiprotic
Propan-2-ol
Acetone 6 Polar and non-hydrogen bond acidic
Diisopropyl ether
Formamide 7 Polar and cohesive
2,2,2-Trifluoroethanol Polar and independent
N,N-Dimethylformaide
Dimethyl sulfoxide
Water

27. Solvents for Reversed-Phase TLC
Solvent Cluster Classification
Acetonitrile 4 Dipolar and weakly aprotic
Methanol 5 Amphiprotic
Propan-2-ol
Acetone 6 Polar and non-hydrogen-
Tetrahydrofuran bond acidic
Trifluoroethanol Polar and independent
N,N-Dimethylformaide
Pyridine

28. Strength Adjusting Solvent
Single solvents do not allow the simultaneous optimization of solvent strength and selectivity
Normal-Phase Chromatography
Weak and Moderately Polar Compounds
n-Heptane
Polar Compounds
Strongest solvent that fails to migrate sample
Facilitates incorporation of solvents immiscible with n-Heptane
Reversed-Phase Chromatography
Always water

29. Solvent Strength Parameter 
Solvent strength parameter for silica gel
= V S A B
Solvent strength parameter for alumina
=-0.226V S A B
Can be used to estimate  values to about 0.04 units for solvents without experimental values
Silica gel is less hydrogen-bond basic and acidic and dipolar/polarizable than alumina
S. K. Poole and C. F. Poole, Chromatographia 53 (2001) S

30. System Maps used to Model Reversed-Phase Separations

31. Totally Organic Biphasic Solvent Systems
Polar Solvent
Counter Solvent
Heptane
1,2-DCE
IPE
OcOH
TEA
Acetonitrile
Dimethylformamide
Dimethyl sulfoxide
Ethylene glycol
Ethanolamine
Formamide
Hexafluoroisopropanol
Propylene carbonate
Methanol
Trifluoroethanol
Ariyasena, T. C.; Poole, C. F. Chromatographia 2013, 76,

32. Selectivity for Biphasic Systems
Totally organic biphasic systems
v < 2
b < 2
System constant values N
Aqueous biphasic systems
v > 4
b > 4
System constant values N

33. Aqueous biphasic systems
Aliphatic
Aromatic
Haloalkane
Acetates
Ethers
T. Karunasekara, C.F. Poole, J. Planar Chromatogr. 25 (2012)

34. Totally Organic Biphasic Systems

36. Models for Normal-Phase Chromatography

37. Localization
Site-specific interactions of both sample and mobile phase components with the energetically heterogeneous inorganic oxide surfaces results in localization.
Localization is the tendency of an adsorbing molecule to become preferentially non-covalently attached to high energy sites on the adsorbent surface
Important for polar compounds, particularly those capable of hydrogen bonding to surface adsorption sites.

38. Localization and Solvent Strength
Solvent Type Solvent strength parameter
(silica) (alumina)
Hexane non-localizing 0 0
Toluene non-localizing
Chloroform non-localizing
Dichloromethane non-localizing
Acetonitrile localizing
Methanol localizing and basic
2-Propanol localizing and basic
Acetone localizing
Diisopropyl ether minor localizing
Methyl t-butyl ether localizing and basic
Ethyl acetate localizing
Tetrahydrofuran localizing and basic
Dioxane localizing and basic
Formamide
2,2,2-Trifluoroethanol
N,N-Dimethylformaide
Water

39. Relative retention (Selectivity)
RM = c – nlog NB
n = the number of localizing groups in the sample
rarely a whole number
NB = mole fraction of strong solvent in a binary mobile phase
Solvent-strength selectivity: Changes in selectivity for compounds with different values of n as the concentration of polar solvent is increased.
Solvent-type selectivity: Arises from differences in the localization of sample and mobile phase components on the adsorbent surface.
Basic and non-basic solvents exhibit different selectivity for hydrogen-bond acids due to sample-solvent interactions in the interphase region

40. Limitation of Models for Retention on Inorganic Oxides
Models fail to separate independent solvent and solute interactions with the solvated adsorbent (RM is a composite parameter)
The simple competition model ignores contributions from solute-solvent interactions in the mobile phase (mobile phase interactions are important)
Active sites on the adsorbent surface have a heterogeneous energy distribution (site-specific interactions)
Steric access to active sites is variable due to their non uniform distribution (steric repulsion)