Common Organic Functional Group Derivatives that Facilitate Work-up, Separation, and Purification

 

The most common functional groups in organic molecules all have some reversible derivatives that exhibit acidic, basic, or heavy metal complexing properties.

• The alcohol group can be converted into an O-sulfate that is acidic. 
• The ketone group can be converted into an oxime that is acidic. 
• The carboxylic acid ester can be converted into an acyl hydrazide which is mildly basic and forms stable isolable complexes with heavy metals.

When these common functionalities are present in a reaction starting material but the planned transformation is occurring elsewhere in the molecule replacing alcohol, ketone, or ester group respectively with O-sulfate, oxime or acylhydrazide often could make no difference at the reaction site but could facilitate the isolation of product from the subsequent reaction mixture. 

Perhaps the reason this is not done is because the potential interference of these derived functionalities is not so well understood while for the parent functions there are usually many precedents. Another reason could be that the ease of work-up, separation, and purification is simply not considered sufficiently important to warrant special facilitation.

Testing Catalysts and Inhibitors to Change the Ratio of a Desired Product and an Undesired Coproduct

Suppose you are working with a reaction step that is providing, rather cleanly, a mixture of two products-- the desired one and an undesired byproduct. Perhaps modifications of conditions are not beneficially changing this product ratio. Perhaps a change in the relative rates of the reactions that give rise to these two compounds can change the final product ratio. Below is a list of molecules that in more than one instance have been found to either speed up a desired reaction or slow down an undesirable one: HMPA, water, N, N-dimethylformamide, N, N, N’, N’-tetramethylurea, urea, dimethylsulfoxide, pyridine oxide, 2-pyridone, N-methyl-2- pyridone, polyethylene glycols, DDQ,  antioxidants, dimethylformamide acetals, 4-dimethylaminopyridine, DBN, DBU,  beta-glycine, EDTA, transition metal salts,  phase transfer catalysts.

For any particular reaction you are trying to improve, most of these additives will have no impact at all. When one of them does exert its effect it can be expected to be effective at low concentrations. For that reason, they can be tested at low concentrations and for this same reason, small groupings of them can likely be tested together.  Any small packet of these additives should be chosen so they do not belong to the same general types. If a group of additives shows some activity in changing the important products ratio only then do experiments need to be done to deconvolute the group to discover which cause the improvement.

For example, I have divided the potential catalysts into five groups, any group of which could be included at a low level in a trial reaction to look for any significant change in the product: byproduct ratio.

A: EDTA, N-methyl-s-pyridone, polyethylene glycol, pyridine oxide

B: DBU, N, N-dimethylformamide, 2-pyridone, transition metal salt

C: Antioxidant, 4-dimethylamino pyridine, dimethylformamide dimethyl acetal, urea

D: beta glycine, N, N, N', N'-tetramethylurea, tetrabutylammonium chloride, water

E: DDQ, DMSO, DBN, HMPA

Probably a better idea is for the experimentalist should consider possible modes of catalysis and choose a group made up of the most likely candidates.

When trying to improve a procedure, improving a method using an additive needs to be considered as much as completely replacing that reaction. 

Acid Traps & Acid Acceptors for Use in Organic Reactions to Remove any strongly Acidic Coproduct

 

If a chemical reaction produces as a co-product a small strongly acidic molecule, the equilibrium of that reaction can be disturbed towards a more complete reaction by trapping that coproduct. 

Acid acceptors and acid traps typically neutralize or otherwise deactivate acid that is already present or that has been created as a coproduct in a reaction. By ‘tying up’ any acid co-product any reversible reaction that involves it is driven to completion and prevented from reversing following Le Chatelier’s Principle.

The following agents have the potential to do this:

Pyridine

2,6-Lutidine

2,6-Di-t-butylpyridine

Poly4-vinylpyridines

Urea

Tetramethylurea

Acetamide forms HBr complex the is insoluble in many organic solvents

Magnesium oxide

Sodium acetate

Calcium carbonate

Mercuric oxide

Ammonium  acetate

Ammonium formate

1,2-epoxy-3-phenoxypropane

Ethylene oxide

Propylene oxide

Epichlorohydrin

Ethylenediamine

Pentamethylpiperidine

1,8-Bis-dimethylamino-naphthalene (proton sponge)

Hexamethyldisiloxane

Trimethylsilyltrifluoroacetamide

Trimethylsilylurethane

4A Molecular sieves

Pyridine ion-exchange resin

Amino Acid Hydrochlorides to Give Zwitterions

N-alkyl-2 halopyridines, formamide acetals, 4A Molecular sieves

Silver oxide

Lead Hydroxide from Acetate: neutralizes acid and gives insoluble salts

Typically acid traps are not bases themselves although all that is essential is that they be substantially less nucleophilic than the moiety that is required to be the nucleophile in the planned transformation. If the nucleophile which is the hoped-for participant in the chemical reaction is readily available and inexpensive the same species can serve in appropriate quantity both as nucleophile and acid trapping agent.

Sometimes the reaction that forms the acid co-product does not involve any nucleophile. Free-radical bromination comes to mind. In this instance, the acid trap must be not nucleophilic at all because it is going to be the strongest Lewis base in the mixture. A substance that forms an insoluble adduct, or which itself is insoluble, or which constitutes a separate phase, or which irreversibly reacts with the acid is desirable. Proton sponge, pentamethyl piperidine, urea, N,N,N',N’-tetramethylurea, and 2,6-di-t-butylpyridine are not nucleophilic.  Magnesium oxide and calcium carbonate are insoluble in organic solvents. Ammonium acetate and ammonium formate are inorganic neutralizing salts that are volatile and so can be pumped away under a vacuum. The four epoxide agents react with hydrogen halides by opening to halohydrins. 

Hexamethyldisiloxane, trimethylsilyltrifluoroacetamide, and trimethylsilylurethane convert free hydrogen halide into trimethylsilylhalide. For this reason, they must be used in sufficient quantity to persilylate any other reactive functional groups in the molecules. Molecular sieves and basic ion exchange resins work by taking free acid into a different phase.

I have used a slightly different idea to remove excess HBr in a process step developed during my industrial career. I added t-butanol to my reaction. It rapidly reacted with HBr as it was formed giving water and non-acidic t-butylbromide.

Glycerol: A Possibly General Method for Changing Solvents in Process Chemistry Reactors

In the laboratory completely changing the solvent that has dissolved within it any mixture of solutes to a different solvent (so long as the solute mixture is stable under the conditions of concentration ) is to completely remove the first solvent on a rotary evaporator, add the second solvent and stir to redissolve any solutes that have precipitated.

This is not even conceivable in industrial reactors because, in almost every case,  they have an appreciable non-stirrable volume. That is to say, when the solvent has not yet been completely removed further evaporation becomes impossible because the impeller blade no longer contacts the liquid. A further problem is that precipitating solutes would accumulate on the walls of the reactor making heat transfer impossible without solute degradation.

 

A possible rather general procedural solution for this difficulty may exist. 

1.    The first reaction solvent is completely distilled (chased) out of the reactor and away from the mixture of less volatile solutes by adding the minimal stirrable volume of glycerol. Glycerol (bp. 290 ℃ with decomposition).

2.    Since neither acetone nor methylene chloride are miscible with glycerol and they do not form any binary azeotrope

 (i) A mixture of some useful proportion of acetone and methylene chloride is added to the glycerol solution or slurry to deliver an upper phase that upon stirring extracts the required non-volatile substrates and the lower glycerol phase is cut away.

or (ii) the desired second solvent, if it is less dense and also immiscible with glycerin, is used to extract the non-volatile substrate, and the lower glycerol phase is cut away.

Then

If (i) above is used, distill the methylene chloride away from the acetone leaving an acetone solution.

If (ii ) above is used, then wash the desired second solvent solution with water or brine to remove traces of glycerin.

Then

If (i)  above has been followed, add the new second solvent and distill away the lower boiling acetone (almost all solvents have higher boiling points than acetone). If this second solvent is to be both protic and miscible with water, residual glycerol needs to have been removed at the stage of the acetone-methylene chloride extract by passing it through a plug of silica or alumina.

Note: For this to work, the mixture of less volatile solutes (usually the entire contents of a reaction mixture ) must be stable in glycerol under the conditions required to evaporate the first solvent and at least the desired components extractable back out of the glcerol.

Improving Phase Separation for Extractions in the Presence of Insoluble Debris

Patent US 5,628,906 explains how to perform rapid liquid-liquid extractive separations in unfavorable situations where there is insoluble debris in the liquid mixture or where there are emulsifying substances present that under vigorous agitation could create emulsions that separate only slowly.

The creative idea of the patent is to mix two fairly miscible solvents to form a superior extractant medium and then subsequently add a third component that causes rapid separation of the total combined solvents into two immiscible phases that can be easily separated. In this way, any surface active agents do not have time to move to the interfacial area and reduce the rate of phase separation, the insoluble debris does not float at the interface and prevent separation and the rate of transfer of substrates between phases is much enhanced.

The method might apply to removing traces of product from a reactor containing insoluble resins by separating the substrates from the surface and interstices of the resin and it could avoid vigorous stirring of the resin slurry that could mechanically damage the resin.

Might it also work in an emulsifier-promoted reaction between a water/acetonitrile solution containing an emulsifier that is reacted with a poorly soluble reagent followed by a phase separation wherein a third solvent that causes phase separation is added? Imagine for example that you are trying to convert cis-cyclooctene into cis-1,2-cyclooctanediol with potassium permanganate reagent.  This would be advantageous because the classical reagent osmium tetroxide is both expensive and toxic.

The problem is that although the substrate is soluble in organic solvents the permanganate salt is not. A mixture of acetonitrile to assist in the solution of substrate and water to get some permanganate into solution could be emulsified with an unreactive emulsifier to bring them pair into intimate contact so they could react. Then addition of a third solvent miscible with acetonitrile but immiscible with water would break the emulsion and cause the separation of two phases despite the presence of the emulsifier. No shaking of the phases together would be required. The potential for a large interfacial layer would be greatly reduced. Because it might also enable the extraction of a water-rich phase with a water-poor phase without first requiring the separation of a precipitate insoluble in both phases, the coproduct, manganese dioxide would be less likely to interfere with phase separation.  

Order of Addition and Other Variables in the Crystallizing or Precipitating Organic Ions as Salts

There are a variety of protocols available for bringing a particular cation and a particular anion together to form a salt that either advantageously crystallizes or precipitates.

Mixing a Stoichiometric Ratio of Acid and Base in a Solvent and:

1. Cooling to a lower temperature
2. Adding a miscible anti-solvent or condensed soluble gas
3. Adding an immiscible  or partially miscible anti-solvent
4. Drowning out in a miscible anti-solvent
5. Slowly adjusting the pH
6. Use of the common ion effect to decrease the salt’s solubility
7. Evaporating to dryness

The Above is the Most Direct and Obvious but there are Other Methods of Formation

1.   Exchange of Ammonium Salt with Nonvolatile Metal Chloride

Exchange an ammonium cation for a different but non-volatile cation selected to create a more insoluble salt of an organic anion and as a coproduct volatile/soluble ammonium chloride.

2. Exchange of formate/acetate/trifluoroacetate/thiocyanate Salt with a Non-volatile Acid

    These four anions have volatile protonated forms. If a     salt of one of these acids is mixed with an organic acid and evaporated to dryness the formic acid, acetic acid, trifluoracetic acid or thiocyanic acid will be driven off leaving a residue of the desired salt.

3. Double Decomposition Reactions

Metathetical reactions between a salt solubilized by the presence of a particular cation and a salt solubilized by the presence of a particular anion to give an insoluble and a soluble salt from which the insoluble salt is recovered by filtration and washing.  The use of metal salts of 2-ethyl hexanoic acid for the basification of organic acids is an example.

Methods for Mixing

1. Direct addition

Addition of a solution of the salt-forming acid or base slowly into a solution or slurry of the product whose salt is sought.

2. Inverse addition

Addition of the salt-capable species, either as a solid or as a solution into at least a full equivalent quantity of the salt-forming reagent.

3. Slow addition of poorly soluble neutral species by extraction

Extraction of the salt-capable species from a Soxhlet extractor by hot solvent and quench of the extracted species by an excess of the salt-forming reagent in the boiler of the extraction apparatus.

4. Impinging Streams of Salt Solution and Anti-solvent

  This is a simultaneous mixing that gives small crystals    that avoids any grinding step to control crystal size

5. Impinging Streams of Acid and Base
   

    This is a simultaneous mixing that gives small crystals that avoids any grinding step to control crystal size  In this situation the neutralizing reaction occurs in the impinging streams.

Methods for Precipitating Salts

1. Crystallization by Diffusion of an Ant-Solvent

Dissolution of the salt in some solvent composition in which it is soluble followed by the addition of a partially immiscible anti-solvent creating two phases wherein the salt is soluble in neither. An example is to dissolve a compound in acetonitrile and then layer it with hexane. Some hexane migrates into the acetonitrile causing crystallization.

2. Partial Evaporation of a Single Volatile Solvent

  The classical method: The components are dissolved in a    volatile solvent and the solvent volume is reduced either by boiling or slowly by evaporation.

3. Lyophilization/Inorganic Salt Removal

Lyophilization (freeze drying) of a solution. Dissolution in methanol and filtration to remove inorganic salts.

4. Slurry to Slurry

The transformation from a slurry of the slightly soluble pharmaceutical acid or base candidate into a slurry of the desired salt form until a method of solution analysis shows equilibrium.

5. Precipitation by pH Adjustment

The dissolving of the pharmaceutical candidate in a partially aqueous solution is followed by the adjustment of the pH gradually by the hydrolysis of a solution component. For example, methyl acetate and base to give acetate and methanol; ethyl carbamate and acid giving ammonia, carbon dioxide, and ethanol.

6. Solvent Expansion

Dissolving the pharmaceutical salt or making the pharmaceutical salt in solution and then exposing the solution to a volatile anti-solvent so that the composition slowly becomes more insoluble.

  7. Evaporative Precipitation

 Dissolving the pharmaceutical salt in a mixed solvent of a less volatile poorer solvent and a more volatile better solvent and then removing the better solvent by distillation.

Process Troubleshooting in Plant and Pilot Plant

 

In the laboratory, some experiments give encouraging results; other results are discouraging. None of these are ‘trouble’ because according to KiloMentor’s definition, ‘trouble’ is an undesired deviation from what was expected that occurs on scale. Undesirable deviations on-scale cost significant money and there is invariably immediate managerial pressure to quickly assign a cause.

 Deviations in quality and quantity are most common. ‘Trouble’ leads to a higher-than-expected cost of goods. That can be fixed by fixing the deviation that caused it or by making other compensating changes rather than fixing the deviation. The former is sometimes the easier course of action.  For example, costs can be reduced by removing a bottleneck in a process to reduce equipment and labor costs rather than fixing a deviation in a reaction yield.

 When talking about deviations we can distinguish two subtypes. 

What I would call a Type 1 deviation is a deviation from a result that has been actually achieved already and that you are trying to reproduce by repeating the protocol exactly, but where the outcome is found to be significantly different. For example, you are repeating a procedure identically, at the same scale, but your outcome is significantly inferior.

What I would call a Type 2 deviation is a deviation from a prior result after making at least one change that one expected and hoped would not affect the result in any deleterious way. It is a deviation from a predicted outcome. For example, using a laboratory protocol you run the procedure in the pilot plant as much the same as possible, predicting a similar quality and yield, but the result is significantly worse. 

Often, established processes are subjected to reevaluation and improvement efforts because even a small yield improvement can lead to a significant financial benefit. In an effort to reduce operating costs, less expensive grades of reagents, solvents, or processing aids are employed and the impurities in these reaction components can have an adverse effect on processing leading to deviations in quality that are deviation from the hoped-for result of no change in quality. If these preliminary experiments are done at laboratory scale, an unfavorable result is a disappointment but is not ‘trouble’ but if the change was accidental or unintentional and was made at scale it is a type 2 variant of ‘trouble’. 

Type 2 deviations also arise in the initial runs of scale-up. Deviations from a hypothetical result may not be deviations at all. The hypothesis that the cases are sufficiently similar to give the same result may be simply wrong. But if we can do something to restore the wished-for expectations it will be wonderful.

Troubleshooting

Troubleshooting is problem-solving under the gun and at scale.

When Trouble happens and you are called to help, treat it as an emergency; act appropriately. Your value to an organization is likely to be assessed predominantly by your skill at troubleshooting when Trouble comes. 

If the trouble stops processing, if possible do not go home until the blockage is removed. Take temporary ownership of the trouble, even if it probably isn’t your fault; assigning blame is not a priority in troubleshooting rather it gets in the way of effective action.  

The most common emergency is a failure in an in-process analytical test or a required observation. Processing, following the batch sheet, stops until a decision on how to proceed is made; you may be required to provide input to that decision. In most instances before applying problem-solving methods to a deviation make sure the deviation is real. Check the analytical method and redo the analysis. Can one confirm the deviation using an alternative analytic methodology? Nothing is more frustrating than trying to find the cause of an unexpected deviation that actually does not exist.

The most frequent error in troubleshooting is called ‘jumping to cause’.  A hypothesis that might explain the deviation comes to mind and immediately the troubleshooters jump into action to test the hypothesis. Only after the hypothesis is proven false and the deviation is not corrected do the scientists consider other hypotheses.  The correct mental process or group protocol is to quickly gather information about the deviating batch and the conforming prior experiments.  Write down in a table form what the deviation is and what it is not. Asking WHAT, WHERE, WHEN, HOW and WHEN NOT, WHERE NOT, WHAT NOT and HOW NOT.  Then construct as many hypotheses fitting with everything that is being observed as one can. Ask whether the hypotheses fit what is known about the problem. Rank the hypotheses from the most probable cause to the least probable.

When there are many hypotheses, the best strategy initially is to combine several changes that are unlikely to have interactions among themselves so that the deviation would be corrected if any one of the changes is the deviation’s cause.  Ordinarily, it is not scientifically preferred to change more than one thing at a time, but here, where a number of the corrective actions can be predicted on the basis of their mode of action to be beneficial or have no effect at all, with no possibility of a negative result, several remediations can be combined.  If the unsatisfactory deviation remains after this trial most likely all the hypotheses combined in the test were untrue. The true cause is probably among the remaining untested hypotheses. 

Often it may be difficult to assign a most probable cause or give a preference to one hypothesis over another. In this situation, one should prefer to test first the hypotheses that are easiest to fix.

When starting a troubleshooting investigation no-one knows how long it will be before the deviation can be corrected.  Often measures are started immediately and in parallel to develop what is called a patch. A patch is an additional step inserted in the process scheme usually to purify off–spec material so that it can be used to carry out further steps of the synthesis.  A patch has value even if it does not need to be used (such as when the cause of the deviation is quickly found), because that patch may be used in the future if a different problem arises. The patch constitutes new purification knowledge about the intermediate. No knowledge is wasted. Developing a patch is insurance. Some deviations are not easily amenable to a patch. When the deviation stops the process completely and prevents one from obtaining any product, even a product of reduced purity, there is nothing to purify further. An emulsion or the complete failure of a solid intermediate to crystallize are examples of deviations that halt processing.

The cause of a deviation may have been hidden by a team member to avoid blame.  Batch records only report what operators 'say' happened. It is possible that a mistake was recognized by operators almost immediately when it occurred, but it was irreversible. It may have been hidden in preparing the batch record. This makes the troubleshooter’s job harder but it is part of human nature and comes with the territory. Operator errors are most likely if some of the operators are replacements for regular workers. In examining a deviation the questions of who and who not needs to be addressed with reference to the operators who conduct the process. Analytical results are almost always generated automatically and overseen by analysts, not operators.  The analytic data are therefore more tamper-proof. 

During scale up there should be many more samples taken than after the process is well established. In the early scale-up stage testing should be planned and carried out at as many different points as possible throughout the processing. The samples should be stabilized and saved for later analysis in case there is a deviation.  These I call forensic samples.  They need not be even looked at when the scale-up experiment goes as expected. At any point in the process step where (i) the mixture is a homogeneous phase and (ii)where the sample will not likely degrade over time under normal storage conditions, consider taking a large enough sample both for analytic testing and also to allow one to continue the processing in the laboratory to see whether the deviation has occurred before or after the sampling point.

When a process step has been finalized and is part of regular production, taking forensic samples can stop. Only retain those that are the in-process checks.  It is true that now if one experiences a new deviation one no longer has these forensic samples to help track it down, but one has the advantage of knowing that since successful runs have preceded this new deviation, the deviation is a real difference from prior practice not just a deviation from one’s expectations based on laboratory results.