pKas of Common Organic Substances.

What does pKa mean? The pKa of a neutral molecule or ion is the negative logarithm of the dissociation constant of a particular hydrogen atom under defined solvent conditions.  Thus for a molecule A with a particular attached hydrogen H that we designate as A-H then Ka=[H⁺] [A^- ] / [H-A] this is the hydrogen ion concentration in the solution multiplied by the concentration of the anion of A all divided by the concentration of the undeprotonated H-A.  pKa is –log Ka = -log [H⁺] –log [A^- ] + log [H-A].  

pKa = pH –log [A^- ] + log [H-A]  

pKa is best understood as the pH at which equal amounts of H-A and A^- exist in the solution. Put another way the pK is the pH at which H-A is one-half deprotonated in the reference solution.

The concept is not just applied to neutral substances or substances that are commonly recognized as Bronsted acids.  Basic molecules are also characterized by pKa values but these are the pKas of the corresponding fully protonated base.

then Ka=[H⁺] [B] / [H-B^+; ] pKa is –log Ka = -log [H⁺] –log [B] + log [H-B⁺] 

Thus pKa= pH –log [B] + log [H-B⁺]   

The solvent systems commonly used are aqueous sulphuric acid for measuring the pKa of strong acids.  The pKas of strong acids are usually negative numbers.  The more negative the number, the stronger the acid.  The strongest commonly known acid is hydrogen iodide.

Water is the solvent used for measuring the pKa of moderate acids and DMSO is common for measuring the pKas of weak acids such as the important class of carbon acids (hydrogens bonded directly to a carbon). 

As an example of the proper interpretation of the pKa acidity of a particular proton, we can note the two pKas important for the common solvent methanol, The pKa of Me-OH₂ is -2.5 and the pKa of the hydrogen bonded to oxygen in neutral methanol, Me-OH, is 15.5.  What the first number says is that at a pH of -2.5 (something like molar sulphuric acid), methanol in the solution is one-half protonated.  The second number tells me that even in the strongest aqueous base (pH 14) methanol is not yet half deprotonated.

Traditional Bronsted Acids	pKa
HI	-10
HBr	-9
HCl	-8
CF3SO3H	-5.1 (-5.9)
HClO4	-5.0
FSO3H	-4.8 (-6.4)
PhSO3H	-2.8
H2SO4	-2.8
HNO3	-1.3
CF3CO2H	-0.6
CCl3CO2H	-0.5
H3PO4	2.1
HF	3.2
H2CO3	3.7

In the same vein, one can look at the pKas of common protic solvents.

Acids with Deprotonated Form as Common Bases	Approx pKa
Isopropanol (isopropoxide)	17.1
t-butanol  (t-butoxide)	18.0
cyclopentadiene (cyclopentandienyl anion)	18.1
acetylene (acetylide)	25.0
triphenylmethane (triphenylmethide)	30.6
diisopropylamine (diisopropylamide)	39.0
ammonia (amide)	41.0
benzene (phenyl lithium)	43.0
ethane (like butyl lithium)	50.0
methane (methyl lithium)	58 ± 5

The table below shows the pKas of different common carboxylic acids.

Acidity of Carboxylic Acids	pKa	Reference Solvent
CF3CO2H	-0.6	water
CCl3CO2H	-0.5	water
HO2CCO2H	1.25	water
Cl2HCO2H	1.35	water
FCH2CO2H	2.60	water
ClCH2CO2H	2.86	water
O2N-Ph-CO2H	3.44	water
HCO2H	3.75	water
HO-CO-OH	3.70	water
PhCO2H	4.20	water
PhCO2H	11.0	DMSO
CH3CO2H	4.76	water
CH3CO2H	12.3	DMSO
H2N-Ph-CO2H	4.92	water
H2N-CO2H	9.8	water

The pkas of the conjugate acids of solvents are a guide to how active a Bronsted acid will be in different solvents, The more negative the pKa the more reactive the proton will be.

Conjugate Acids of Possible Solvents	pKa
CH3SCH3	-6.99
CH3O-Ph	-6.5
Ph-COOEt	-6.2
CH3OCH3	-3.8
(CH3)2CO	-2.85
CH3OH	-2.5
H2O	-1.7
CH3SOCH3	-1.5
NH2(CS)NH2	-1.26
H ( CO )NH2	-0.48
CH3(CO)NH2	0.1
NH2(CO)NH2	0.5
NH2CH2CO2H	2.35

Probably the most valuable table is the one showing carbon acids alongside other reference acids. This helps when deciding how strong a base is required for a particular deprotonation.

Organic acids	pKa
PhSO2H	1.2
PhCH=NHOH (a protonated oxime)	2.0
MeSO2H	2.3
HNO2	3.4
MeCOSH	3.4
H2CO3	3.7
P{hCH2NH2OH (a protonated hydroxylamine)	4.9
PhNHMe2 (protonated dimethylaniline)	5.1
PyrH (protonated pyridine)	5.2
MeNH2OH (protonated N-methyl hydroxylamine)	6.0
Thiophenol	6.5
H2S	7.0
phthalimide	8.3
PhB(OH)2	9.0
acetylacetone	9.0
ammonium ion	9.2
succinimide	9.6
NH4CO2 (carbamic acid zwitterions)	9.8
Phenol	10.0
Nitromethane	10.0
bicarbonate	10.2
Thiophenol (in DMSO)	10.3
Ethanethiol	10.6
Cyclohexyl ammonium	10.7
triethyl ammonium	10.8
2-carboxyethyl cyclohexanone (beta keto ester)	10.9
acetone enol	11.0
Diethylammonium	11.0
Dicyanomethane	11.4
Hydrogen peroxide	11.6
2-indanone	12.2
PhCH2NO2	12.3
CF3CH2OH	12.4
Methyl cycanoacetate	12.8
guanadinium ion	13.4
ethylacetoacetate (DMSO)	14.2
imidazole	14.5
methanol	15.5
water	15.7
ethanol	15.9
Phenylacetone	15.9
acetaldehyde	16.5
2-nitropropane	16.9
isopropanol	17.1
t-butanol	18.0
cyclopendadiene	18.1
thioacetamide	18.5
acetone	19.2
nenzylcyanide	21.9
diphenylamine	23.5
chloroform	24
phenyl methylketone	24.7
acetylene	25
acetamide	25.5
urea	26.9
3-pentanone (DMSO)	27.1
Phenyl methyl sulfone (DMSO)	29.0
ethyl acetate	30.5
triphenylmethane	30.6
2-phenyl-1,3-dithiane (DMSO)	30.7
Dimethylsulfone (DMSO)	31.1
acetonitrile (DMSO)	31.2
diphenylmethane (DMSO)	32.3
N,N-diethylacetamide (DMSO)	34.5
diisopropylamine (THF)	35.7-39
ammonia	41
toluene (DMSO)	43
benzene (CHA)	43
ethylene	44
propylene	47.1-48.0
ethane	about 50

Trituration with a Modified Water Phase as a Potential Chemical Process Development Method

A reaction may proceed quite well to give an 80% yield of the desired product but be very difficult to work up if it is a mixture of neutral compounds. In this situation acid-base extraction cannot help to obtain some partitioning between organic and aqueous phases.

Furthermore, most often the two main compounds making up the reaction mixture are both essentially insoluble in water.  When there is 20% by weight of an impurity, even when you can find a solvent that gets the major compound to selectively crystallize, the recovery is usually poor simply because by the time you have crystallized 60% of the major compound the mother liquors are a 1:1 mixture of desired and undesired compounds. At this point, the rate of crystallization normally becomes impractically slow, and for practical purposes, the crystallization has stopped. 

Usually, thin-layer chromatography in more than one solvent system can quickly tell you whether the main impurity, which most probably is the one blocking the crystallization, is, by and large, less polar or more polar than the desired major component.  When the minor component is the more polar, what we intuitively would like to do is triturate with water, modified so that it can dissolve more of the mixture, hoping that the additional material dissolved into the water-rich phase will be disproportionately the more polar impurity component. 

Hydrotropes can work by salting-in some compounds.

In another way, a co-solvent for water can be effective so long as it prefers to mix with the water rather than forming an oily phase with the products.  Only experimentally can we find something guaranteed to work, but perhaps KiloMentor can propose a rule of thumb, which could increase the likelihood of success. This aqueous phase modifier should be completely miscible in all proportions with water.  If a diluent is only partially miscible with water it is more likely that when mixed with the neat reaction oil it will simply migrate into the oil. 

The most lipophilic solvents that are completely miscible in all proportions with water are: acetone, methyl ethyl ether, methyl acetate, and t-butanol. The lower homologs of each of these function group types will also be completely miscible. That is: methanol, ethanol, propanol, and isopropanol are also completely miscible and could be used as diluents. With esters, ethyl formate is not completely stable in water so it should not be used. Acetonitrile is completely miscible but propionitrile is not. Nitromethane is not completely miscible, while dimethylformamide, N-methyl formamide, formamide, DMSO, and pyridine are.

In addition to adding small quantities of these solvents to a large excess of water to increase the leaching power of the polar phase, recrystallization from the less polar of these, at least: acetone, t-butanol, pyridine or methyl acetate, by the gradual addition of water, could be fruitful.

Once the level of the impurity is reduced below 10% from the 20% range, crystallization, in general, can be expected to give a much-improved recovery.  From a mixture containing just 10% impurity, one could crystallize 80% of the major component before the mother liquors would be 50:50 product: impurity.  

Even on scale, a reaction mixture can be freed of organic solvent by concentration in the presence of a water phase to give a reaction product oil as an oil in water. The aqueous phase modifier could be added into this mixture to achieve an in situ trituration.

When trituration is not working, an alternative is to dissolve the compounds into isooctane and extract with some mixture of acetonitrile, water, or ethylene glycol.

Crystallization from a Separation Perspective

Crystallization is the most frequently used method for isolating organic solids. Recrystallization is the most frequently used means to purify them. But this phase switching from a solute in solution to an ordered solid is one of the most unpredictable methods both for isolation and purification in the sense that it is impossible to predict melting point, solubility, or lattice energy much less the comparative values of these for the desired product versus t the most troublesome by-products which one is trying to remove from the reaction mixture from which it was synthesized. This unpredictability is exactly what led KiloMentor to focus on other ways to switch phases to achieve purification in a chemical process chain.

This is not to say that once a certain molecular architecture has been achieved one cannot prove that the target compound is a solid. I am saying first, that no reliable prediction can be made of how to get it separated sufficiently pure that it is not an oily mixture, and second, no reliable prediction is possible of what recrystallization conditions will be needed to purify it from its most predominant and intransigent impurities and, third, what yield of pure product can be anticipated. 

The following generalizations have some logical basis:

The lower the melting point of an intermediate, the more difficult it will be to crystallize. 

There is a positive correlation between melting point and ease of crystallization. 

The presence of impurities in a reaction mixture leads to a melting point depression and contamination of isolated samples of the desired product.  

The extent of the melting point depression depends upon the proportion of those impurities. 

The free energy of crystallization is roughly proportional to the enthalpy of crystallization and this is roughly proportional to the melting point.

The fewer the chemical conformations (the fewer the rotatable bonds) or the more symmetrical the compound, the more crystallizable the compound will be.  

I do not know whether this is latter claim is proven but it seems likely and agrees with some simple observations. Compounds with long hydrophobic chains as part of the structure tend to be lower melting than cyclic substances. Compounds with high symmetry seem to be higher melting than unsymmetrical compounds of the same molecular weight and functional group type (ie t-butanol vs 1-butanol).

This makes sense in physical terms.  There would be more entropic resistance to the crystallization of a molecule that can adopt multiple conformations than to one that because of its cyclic form or symmetry can adopt fewer.  If only one conformation can be accepted into a crystal lattice, the compound with fewer conformations has a statistically better chance of being added to the lattice.  Thus crystallization might be expected to be faster.

Crystallization is accelerated if one has seed crystals and it is for this reason that so much effort is expended to get the first crystalline material.  If an intermediate has never been prepared before one should anticipate the possibility that a considerable effort may be needed to obtain the first solid. The methods adopted to obtain the first batch of material sufficiently pure to crystallize do not need to be scaleable. Making these seeds is a valid use of chromatography in process development.  Column chromatography can quickly and dependably deliver a high-purity material, which should have a significantly enhanced tendency to crystallize.  If a chromatographically purified solid material does not readily crystallize one has good reason for pessimism.

Other classical methods which can lead to that initial crystallization are:

• scratching the flask containing the impure material with a glass rod while cooling the oil
• steam distillation to remove traces of solvent from the oil
• ultrasonic treatment in a sonification bath
• cooling to a low temperature to form a glass followed by slow warming
• trituration with a pure hydrocarbon fraction
• overnight cooling in a sealed vessel (to exclude moisture) in a deep freeze
• formation of a solid derivative, crystallization, followed by regeneration of the compound itself

It is apparent why this should happen if the initial crystallization is being inhibited by small amounts of a particular impurity.

The difficulty with the initial crystallization of a new substance is that two different physical processes must occur in each other's presence. First, initial crystal nuclei must be generated and this usually requires a low temperature AND then, second,  these nuclei must become bigger. This latter requires crystal growth. The optimum temperature for crystal growth is consistently more elevated than the best temperature for nucleation.  It is for this reason it is thought that raising and lowering the temperature or establishing a temperature gradient within the oil or solution can enhance this first crystallization. Seeds formed in one colder region of the oil or solution migrate into the warmer crystal-growth region.  

Once some crystals have been created, even when one performs a recrystallization there are always, it is hypothesized, trace amounts of the crystals remaining that, as seeds, provide a ‘memory’ when the bulk of the material is taken to conditions optimum for crystal growth. This explains a remarkable phenomenon. One form of crystal may reproducibly form from a substance for years but then by chance, a more stable form crystallizes and thereafter it is impossible to obtain any of the first form because there are always seeds around to catalyze the formation of this later-discovered but more stable form.

Coloured compounds which according to their structure should not be coloured are contaminated by small amounts of polyunsaturated impurities.  Charcoaling can remove the colour and at the same time often assist that initial crystallization.

Crystallization is an art. There are the virtuosos and then there are the rest of us.

Low-Temperature Crystallization

In the laboratory, crystallizing and then reducing the temperature of the crystal slurry to below zero and filtering below zero is quite likely to fail. The reason is that, at the laboratory scale, working with one's hands, it is difficult to maintain an inert atmosphere over the cold liquid and over the filtered crystals. This causes moisture to condense into the crystallizing mixture and onto the solid already collected on the filter funnel and this can lead to outright failure, oily crystals, or a solid that melts away on the filter or dissolves in the wash liquid.

At scale, however, these problems are eliminated. It is simple to retain an inert atmosphere which excludes moisture. It is simple to cool to sub-zero temperatures and hold that temperature; and it is much easier to hold the temperature of the filtered solid low and also keep cold the temperature of the wash liquid.  Using a temperature differential between the boiling point of the solvent on the upper side and –20 ℃ on the lower side can provide higher recoveries of crystalline product. Also, the greater temperature gap is less demanding on the solvent properties and allows more inexpensive solvents to function adequately.

Using less common solvents at scale should be more a case of selecting a solvent for improved purity rather than choosing a solvent for enhanced recovery.

Checking for the purification ability of a solvent operating on a particular reaction mixture

If the problem of obtaining crystals of the product from the mixture is resolved, it is useful to explore the ability of the solvent to distinguish between the desired intermediate and other impurities in the reaction mixture which one would expect. The following experiment might be very revealing and very simple to do, but frankly, I have never done it myself and I know of no one who has ever done it.  Take a crude solid contaminated with reaction contaminants and divide the solid into two equal portions.  Recrystallize the first portion from the solvent you have identified. Filter the solvent but do not allow any wash liquid to mix with the mother liquors but keep the mother liquors from this first crystallization separate. Dry the solid. Now use the mother liquors to recrystallize the second portion of the solid and isolate it in the exact same way. Now compare the recovery and purity of the two portions. The recovery of the second portion would be expected to be higher than the first. The second recrystallization presumably is done from solvent already saturated with the desired product. The purity of the first should be greater than for the second. There will be nearly twice the level of impurities in the second crystallization versus the first; however, the extent of these differences will be quite dependent upon the particular substance and its particular impurity levels. Thus, one experiment might provide a very good idea of how much recycling solvent could improve recovery for a process step.

A crystallization in two parts followed by a trituration or slurrying of both parts combined in an anti-solvent might be expected to give a better yield of a homogenous product in a single batch than some of the poor recovery recrystallizations that we often employ.