Transition Metal Complexes for Chemical Process Development: In Particular Reinecke's Salt

Isolation Methods Most Important

KiloMentor takes the position that, in the present state of the chemical arts, electronic database searching has enabled chemists of ordinary skill to design ingenious reaction schemes by little more than electronically searching for reactions to string together. It is isolation and purification procedures where there is the least literature support for individual acuity. Isolation methods cannot be searched because the search terms are the solution to the problem, not the starting point.

Therefore KiloMentor wants to emphasize where inexpensive transition metal complexes such as those with Chromium (III) and Cobalt (III) can simplify the work-up of chemical process steps.

Chromium(III)  Complexes Kinetically Available

Chromium (III) is the most stable and important oxidation state of the element in general and particularly in aqueous chemistry.

 Advanced Inorganic Chemistry 1966 pg. 823 states, “The foremost characteristic of this state is the formation of a large number of relatively kinetically inert complexes. Ligand displacement reactions of Cr (III) complexes are only about 10 times faster than those of Co(III), with half-times in the range of several hours. It is largely because of this chemical inertness that so many complex species can be isolated as solids and that they persist for relatively long periods of time in solution, even under conditions where they are thermodynamically quite unstable.”  

Note that it is the kinetically inert property of chromium complexes that makes them valuable. This is saying that complexes that are not the thermodynamically most stable nevertheless can be isolated.  This means more compounds are in principle accessible.

Cobalt Complexes Likely Most Useful

 About cobalt chemistry, Advanced Inorganic Chemistry 1966 pg. 873 says “The complexes of Cobalt (III) are exceedingly numerous. Because they generally undergo ligand exchange reactions slowly, but not too slowly, they have, from the days of Werner and Jørgensen, been extensively studied and a large fraction of our knowledge of the isomerism, modes of reaction, and general properties of octahedral complexes as a class are based upon studies of Co (III) complexes.” 

What I take this to be saying is that many different complexes of cobalt would, in principle, also be readily accessible.

Iron Complexes Don't Work for Amines

Iron also appears to be promising in terms of offering multiple potential complexes.  Iron (III) forms a large number of complexes, mostly octahedral ones, and octahedrons may be considered its characteristic coordination polyhedron. The affinity of iron (III) for amine ligands is very low. No simple amine complexes exist in aqueous solution. For example, the addition of aqueous ammonia only precipitates the hydrous oxide. Chelating amines like EDTA do form some definite complexes among which is the 7 coordinate [Fe(EDTA)H2O]ion. Also, other amines such as 2,2’-dipyridyl and 1,10-phenanthroline that can produce ligand fields strong enough to cause spin-pairing, do form fairly stable complexes isolable in crystalline form when combined with large anions such as perchlorate.

Other Transition Metals in Organic Synthesis

Transition metals now have an extensive application as catalysts in organic chemistry.  Nickel, palladium, and platinum complexes are today extensively used to catalyze reactions for which there are no uncatalyzed equivalents.

Extensive chemistry has also been established centering on the practical question of the recovery and recycling of the noble metal catalysts, mainly palladium, and platinum, since these represent expensive inputs into a process.

From the KiloMentor perspective of using transition metal complexes for isolations the complexes of the wide variety of less expensive chromium, cobalt, and iron complexes would seem most promising.

 Reinicke and Rhodanilate Salts:

The Chromium Salt NH4[Cr(NH3)2 (SCN)4] called ReinickeSalt is red in color. It is soluble in ethanol or hot water and it is reported to dependably yield precipitates with primary and secondary amines. The implication of many reference books seems to be that the salt does not form precipitates with t-amines, but this is false. According to Cotton & Wilkinson’s Advanced Inorganic Chemistry Comprehensive Text, it can be used, in general, to precipitate large cations, either organic or inorganic. It seems likely however that although, thermodynamically, precipitation of Reinecke salts may not be as selective as has been publicized, fractional precipitation based on rates of precipitation can provide purification as suggested for the closely related Rhodanilate salts (see later for Rhodanilate definition).

The Reinecke and the related Rhodanilate salt possibly could be used to precipitate particular amines in the presence of others. One idea is that because the Reinicke salt is soluble in alcohol alone, a useful separation could be done on a substrate, which is sensitive to water. A useful application of this might be to apply a  difference in rates of precipitation to selective precipitate starting amine after performing an N-alkylation. 

Amines are frequently used as reagents to neutralize acidic co-products of a reaction and thereby drive any equilibrium in a particular direction. The most frequently used amine in this regard is triethylamine.  Some advantages of triethylamine are that even if it is employed in excess any unused base is

i)             volatile enough to be removed by vacuum

ii)             water-soluble enough to be carried away in a water wash

iii)           inexpensive enough to be discarded and

iv)          easily made anhydrous.

The disadvantages are that it is volatile enough to escape from reactions that require heating and nucleophilic enough to compete in some displacements and deprotonations. Employing the Reinicke or Rhodalinate salts in a work-up of mixtures containing more complex but more expensive amines may make them recoverable and recyclable; and so practical as traps for acidic coproducts.

Another possibility is that the initial formation of an easily isolable amine salt of a complex anion X could be followed by the switch from the amine salt to the inorganic metal salt via a Reinecke or Rhodalinate reagent which could precipitate the intermediate amine.

For example, a salt of an amine with a complex anion X might be converted into the salt of a metallic cation MX by adding that M in the form of acetate and precipitating the amine (here R3N) as the Reinicke salt precipitate. The ammonium acetate could be removed by evaporation since both ammonia and acetic acid are volatile.

M^{+ -} OAc  + R3NH⁺ X^- + NH4[Cr(NH3)2 (SCN)4] going to

R3NH [Cr(NH3)2 (SCN)4] (insoluble) + NH4 OAc  + M X

I do not know of any experimental examples of this, however.

Amine Recovery from Lithium Amide Reagents

The lithium salts of many sterically hindered secondary amines, such as lithium diisopropylamide, are used for quantitative deprotonation in chemical synthesis. Because they are sterically hindered the resulting secondary amine co-products do not interfere in subsequent reactions of the carbanions they helped create. These sterically hindered secondary amines may need to be separated from the desired product in the reaction workup and if they are expensive. recovered for recycling. Reinicke Salts, Rhodanilate salts or Trisoxalatochromate salts can potentially be used to precipitate these secondary amines and remove them as filterable solids. Diisopropylamine, dicyclohexylamine, 2,2,6,6-tetramethylpiperidine, isopropyl-cyclohexylamine, and pentamethylpiperidine need to be examined to see whether they can be quantitatively or semi-quantitatively precipitated.

Proline and Hydroxyproline Isolation with Rhodanilates

According to Max Bergmann’s article in J. Biol. Chem.109, 471 (1935), proline and hydroxyproline can be precipitated from gelatine hydrolysates using Reinecke’s salt and the amines liberated by forming a complex with N,N-dimethylaniline or pyridine. This liberation shows that all amines can react.

In this Bergmann article the formation of what he regards as more selective complexing agents are achieved by replacing the ammonia ligands with other amines. Displacing the two ammonia with aniline gives what is called ammonium rhodanilate.  About this Bergmann says, “ Rhodanilic acid forms rose-colored, well-crystallized salts with basic nitrogen compounds, and in particular with alkaloids and with amino-acids. Although rhodanilic acid lacks definite specificity, the various rhodanilates differ greatly in their solubilities, crystalline form, and rate of crystallization. It is therefore often possible to separate from mixtures of amines, amino acids, or peptides, single homogeneous products by fractional precipitation with rhodanilic acid. In fact in  cases where several rhodanilates form simultaneously, a separation by fractional crystallization is often possible.”

With regard to the amount of ammonium rhodanilate in the fractional precipitation Bergmann says that “The quantity necessary was determined by examining the precipitate under the microscope in the course of successive additions.” 

I interpret this to mean that the precipitation was controlled by the kinetics and the fastest precipitating compound came out first essentially alone followed by other compounds and the precipitate was collected in fractions that were subsequently combined on the basis of their microscopic crystal shape.

In the case of preparing proline rhodanilate, the free amino acid was simply achieved using excess pyridine.

“In order to obtain the free amino acid from proline rhodanilate, advantage was taken of  the fact that pyridine rhodanilate is very difficultly soluble in water. It is therefore sufficient to suspend the solid proline rhodanilate in water and to add a little pyridine  in order to precipitate almost instantly the entire rhodanilic acid as the pyridine salt. On filtration, a faintly colored aqueous solution of l-proline is the residual.

The by-product of such a purification is pyridine rhodanilate. It may easily be recycled  into ammonium rhodanilate with ammonia and so recovered for further use.

Thus ammonium rhodanilate can be used to precipitate a complex amine, the amine rhodaniliate can be freed from the complex with pyridine to precipitate the very poorly soluble pyridine rhodanilate and then the ammonium rhodanilate can be reformed from the pyridine salt by treatment with excess ammonia.

Cleaning Mercury Traces from Wastewater

In a final use, of the Reinicke salt, if mercuric acetate bound to an ion exchange resin is used as a source of mercuric ions in a reaction. Water from such a reaction, that could contain small amount s of mercury ion, can be decontaminated with Reinicke Salt which precipitates the mercury ion.

Potential Uses of Tannic Acid

Tannic acid is a cheap natural product available from Aldrich. Synonyms are Gallotannic acid, Gallotannin, Galloylglucose, Glycerite, Quebracho or simply Tannins. It has in the past been used to make slow release pharmaceutical products, but that is long gone because the natural variability of the mixture of components leads to a pharmaceutical salt having too much inconsistency in its certificate of analysis.

The molecular weight of tannic acid is usually in the range 1250-1700. Natural tannin is typically derived from Turkish or Chinese nutgall.

Tannin is a polyphenol. It can also be regarded as a natural dendrimer of gallic acid with branching groups built on a scaffold of glucose. It forms a highly concentrated solution in water. One gram can dissolve in 0.35 ml of water according to the Merck Index. It is also soluble in glycerol and lower alcohols such as isopropanol and acetone while being insoluble in non-polar solvents.

Tannin is known to precipitate alkaloid as salts. There are other useful things it is likely to do usefully but for which now that I am retired I do not have the search tools to find evidence. For example, the molecule, because of its polyphenolic nature, might be expected to:

·        Trap halogens and make products that either dissolve in water or precipitate: therefore, tannin added to a wash layer would be expected to remove the colour of residual halogen agents.

·        Precipitate some other polymers; for example, it is known to precipitate albumin, starch, gelatin which are water soluble proteins or carbohydrates.

·        Precipitate small molecular weight water soluble amines as tannic acid salts.

·        Precipitate polyethylene glycol. 

with regard to this last idea, polyethylene glycol (PEG) preferentially binds with tannins to form an insoluble precipitate  [Jones, W. T., and J. L. Mangan. 1977]. Complexes of the condensed tannins of sanfoin (Onobrychis viciifolia Scop.) with fraction 1 leaf protein and with submaxillary mucoprotein and their reversal by polyethylene glycol and pH. [J. Sci. Food Agric. 28:126–136.]

There are other questions:

·        Would it quench free radical oxidants and remove the metal into an aqueous solution or precipitate it?

·        Would tannic acid remove boric acid by forming borate esters with the 1,2-diphenolic unit?

·        Would it remove chromium by treating an organic layer with an aqueous solution?

·        Would it complex hypervalent iodine?

·        Would it remove formaldehyde?

·        Would it react with aldehydes?
Would it quench residual diazonium salts at the end of a reaction?

Siderophores are 1,2-dihydroxybenzene containing materials. Metals chelated by siderophores are Aluminum, Gallium, Copper, Zinc, Lead, Tin, Manganese, Cadmium, Vanadium, Indium, Plutonium and Uranium.

Sodium borohydride might be beneficially worked up using a solution of tannic acid in water or ethanol. In some applications it is very important not just to destroy the borohydride anion but the borane that results.

Tannic acid, I would expect, would potentially destroy cyanide salts because they would attack the phenolic esters. It is known that tannic acid reacts with formaldehyde. Similarly, I think, the catechol functionality would react with other aldehydes.

What would an aqueous solution of tannic acid do with a basic ion-exchange resin? Because of the tannic acid component's significant size it could not enter the smaller voids in the resin. It would however, because of its acidity, develop ion pair bonds that would hold the polymers together.

Tannic acid also forms insoluble complexes with polyvinylpyrrollidone, a behaviour that suggests binding to amide carbonyls where it can share hydrogen atoms in strong hydrogen bonds.

Would tannic acid adsorbed on PVP be useful for removing traces of dipolar aprotic solvents from organic solvent streams?  Because gallic acid units are very electron rich, tannic acid might readily extract electron deficient charge transfer agents into an aqueous solution of tannic acid.

Phenols form strong hydrogen bonds with p-dioxane. Would tannic acid be
soluble or insoluble in dioxane?

Along the same line of thought, might a solution of tannic acid form hydrogen bonds that could complex triphenylphosphine oxide and help remove it from a difficult work-up?

The special characteristics of being both a polymer, and a polyphenol while being at the same time a cheap material suggest that tannin may have many as yet untested uses.

Urea Complexes for the Separation of Straight Chain Solvents

In a recent blog pertaining to solvent replacement, ”Solvent Replacement: the need to change solvent either from a reaction solvent to a crystallizing solvent or during reaction telescoping in a process” April 9^th 2007, KiloMentor suggested the possibility of using a high boiling n-paraffin, or dibutyl ether, or a polyethyleneglycol as a chaser and then removing that solvent as a urea inclusion complex.

I proposed this, not as an established or even exemplified procedure, but only as something that might be expected to work.  A paper has appeared, commenting again on the need and the difficulty of removing high boiling dipolar aprotic solvent residuals when isolating pure reaction products [Removal of Reaction Solvent by Extractive Work-up: Survey of Water and Solvent Co-extraction in Various Systems, Laurent Delhaye, Attilo Ceccato, Pierre Jacobs, Cindy Kottgen and Alain Merschaert. Organic Process Research & Development, 2007, 11, 160-164.] This article was published on the web

 http://pubs.acs.org/cgi-bin/abstract.cgi/oprdfk/2007/11/i01/abs/op060154k.html

 Perhaps one solution will be found using dipolar aprotic solvents that are effectively linear and longer than eight atoms because it is these molecules which can be cleaned out of the final product using urea complexes.  I would like to offer some further literature support for this idea now.

Urea complexes of polyethylene glycol, dibutyl ether, octadecane and diethylene glycol are known in the literature are made in the established way. Also the literature already provides experimental details for making urea complexes of the n-paraffins from light gas-oil and heavy gas-oil petroleum fractions. [Ind. Eng. Chem. Res. 1997, 36, 3110-3115. Separation and Characterization of Paraffins and Naphthalenes from FCC Feedstocks,  A.A. Lappas, D. Patiaka, D. Ikonomou and I.A. Vasalos]. The paper teaches the separation of the n-paraffin fraction from fluid catalytic cracking using urea. This teaching encourages one to suspect that n-paraffins, even when present as a substantial portion of a mixture as it would be if it were the residual solvent after a concentration, can separated from other mixture constituents.  Sufficient urea would be added along with a polar compound (activator ) such as water, aliphatic alcohol, or ketone which expedites the completion of formation.  Methanol is usually used.

The procedure provided in the paper is quoted:

“Separation of n-Paraffins by Urea Adduct Formation.

 The entire separation procedure for the non-aromatic fraction is described in Figure 1.  The typical removal procedure of the straight chain hydrocarbons (n-paraffins) from heavy or light gas-oil is

 (i) 15 g of urea and 5 g of HGO (or (LGO) aliphatic hydrocarbons (isolated by elution chromatography-ASTM D-2549) are placed in a 250 ml flask and stirred for 0.5 h at 55-60 C by adding 25 ml of methanol and

 (ii) the mixture is stirred for 1.5 h in room temperature and for 0.5 h at 10 C. The solid adduct is washed with hexane (60 ml) and filtered off.”

The commentary on this procedure in the paper was:

“….The key factor which affects the entire procedure is the effective contact between urea (or thiourea) and the paraffinic substances.  This contact is influenced by the amount of excess urea and methanol. The following excesses are necessary for satisfactory separation/;25 ml of methanol and 15 g of urea for paraffin separation …….The stirring of mixtures at some very specific temperatures is also very important.  The initial heating must be at 55 C for a period of 30 minutes.  This serves to increase the rate of adduction of the heavier n-paraffins through increased solubility and diffusion in the methanol-urea phase.  By decreasing the final adduction temperature to 10 C, the recovery of compounds such as C₁₃ and above is improved…..”

It would seem that this advice can be useful devising conditions to remove uniform molecular weight, high boiling, straight chain solvents.  In fact this should be a simpler case.  A single optimal temperature for adduct formation tailored to the particular solvent and another temperature to maximize yield for filtration could be expected to work well.  What only experimentation can discover is to what extent solutes, from any particular reaction mixture being isolated from the high boiling solvent, are selectively excluded from the urea complexes.

Besides the straight chain high boiling solvents already mentioned we can imagine diglyme, triglyme and tetraglyme behaving effectively the same way.

The following articles show examples of these molecules forming complexes.

Redlich, O.; Gable, C.M.; Dunlop, A.K.  and Miller, R.W..  Addition Compounds of urea and organic substances. J. Am. Chem. Soc. (1950), 72, 4`153-60

Topchiev, A.V.; Roozenberg, L.M.; Nechitailo, N.A.; and Terent’eva, E.M., Khurnal Neorganischeskoi Khimii (1956), 1, 1185-93. (Russian)

C.A. 49, 11559b.

Geiseler, Gerhard; Richter, Peter. Urea-adduct formation of position-isomeric n-alkane derivatives. Chem. Ber., (1960), 93, 2511-21.

Hild, Gerard. Macromolecular addition compounds. I. Research on urea (or thiourea) addition compounds with poly (oxyethylenes). Bulletin de la Societe Chimique de France (1969), (8), 2840-54.

Using Separation Techniques to Get a Short Synthetic Procedure

Potential One Step Synthesis of 6,6-dimethylcyclohex-2-enone

My B.Sc. project at Carleton University in 1967 was the synthesis of 6,6-dimethylcyclohex-2-enone. One of the literature procedures was a one step synthesis from methyl isopropyl ketone and acrolein published by J. Colonge, J. Dreux and M.Thiers, Compt. Rendu. 243, 1425 (1956). The reported literature yield was just 12%.
When I attempted to repeat the procedure the product mixture in my inexperienced hands was either entirely or largely intractable with the volatile portion comprising 11 separate GC peaks, four of which were relatively large. Forty four years later I would like to reexamine how  this synthesis might be reasonably pursued.
The alternative route was six steps long. If the average isolated yield is 80% then the overall anticipated yield would be (0.8)6 = 26.2% for this longer route. The routes are comparable in yield. The time and cost of chemicals would be substantially less for the one step route. The question is can the terrible mixture expected from the acrolein condensation be separated reasonably on scale. Let us set devising a protocol to get clean product out of such a mass as the challenge.
The reaction was performed between methyl isopropyl ketone and acrolein. The acrolein is a neat liquid stabilized against polymerization with hydroquinone. The main by-products will likely arise from the polymerization of acrolein. The trick will be to get the ketone to react with the acrolein before the acrolein is destroyed by polymerization. When the reaction time is over the mixture must be cooled and neutralized. The presence of a free radical inhibitor such as galvinoxyl that is not interfered with by the methoxide base would seem wise.
The working out of the most preferred ratio of reactants and the most preferred mode of bringing them into reaction is a separate question and not the key one I would say. Critical is how are we going to separate the terrible mixture? The good news for this synthesis is that the poor yielding step comes at the beginning of the sequence- in fact the reaction constitutes the entire process. One will not be carrying along material that eventually becomes part of waste after numerous process stages. The waste will be formed quickly and not have extra work expended upon it!
The mixture will contain the degradation products of acrolein and sodium methoxide and the free radical catalyzed polymerization of acrolein to give CH2=CH-CO-[(CH2)2CO]n-(CH2)2CHO.The dimer of acrolein would still remain. The products of Cannizaro reactions involving the methoxide acting as a reducing agent are also possible. The main characteristic of the by-products would be that they are fairly high molecular weight. It might be desirable to quench with a mild reducing agent that will only hit aldehydes. The desired product is in fact distinguished in that it does not have aldehyde. Once the kill solution has been added steam distillation is likely to separate volatile materials from polymers. The desired alpha-beta unsaturated ketone if formed woulld be in this distillate. The main constituent of the steam distillation will be starting methyl isopropyl ketone. The recovered starting material can be separated from desire product by reaction with diethylamine. Only the alpha beta unsaturated carbonyl will react with the base by Michael addition and the product will become soluble in weak aqueous acid. The unreacted methyl isopropyl ketone will remain as the organic phase.
Upon back extracting the neutralized base into an organic layer it can be directly methylated. With base the quartenarized amine may be lost to return the unsaturated ketone. Unreacted beta amino compound is separable again by acid-base extraction.

Wolf & Lamb Reactions or Site Isolation Reactions

Wolf & Lamb reactions are reactions or reaction sequences wherein at least two mutually reactive agents are kept in the same reactor isolated from each other by being attached to separate solid phases, which cannot interpenetrate each other.  For example one polymer may have an oxidant attached to it while another solid in the same reactor has a reducing agent attached to it but they cannot react with each other because each is held on a separate resin or porous solid. Alternately a strong base containing for example triphenyl methylide anions may be on one resin and the second resin may have acidic groups bound to it.

What is the characteristic of a transformation or set of consecutive reactions that can be performed more efficiently in a medium providing this site isolation possibility?

We can imagine a mental cartoon in which a Substrate (S) moves to an immobilized reaction site and a reaction happens there because

i) there is a reagent tethered there

ii) the environment there is different (pH, solvent composition, ionic strength)

iii) there is a catalyst immobilized there

iv) there is a trapping agent for a functional group there (this last possibility applies more to the product of a reaction on another immobilizing solid)

Intuitively some uniomolecular isomerizations with no change in formula:

oxidations (loss of electrons, loss of hydrogens, addition of oxygen)

reductions (addition of electrons, addition of hydrogen, loss of oxygen)

base abstractions using a polymer supported base

dehydrations

dehydrohalogenations

sulfonation using pyridine sulfur trioxide

halogenation

transfer metal carbonylation e reactions seem likely to be advantageous:

Why would this situation be advantageous?

The reagent could attack another reagent present in situ if both were not immobilized

there are two competing reactive functionalities in the same substrate and the less reactive functionality will compete with the more reactive unless the desired product is trapped out on a separate resin.

the product of a reaction can react with the starting material if it is not trapped out on a separate resin to keep it away from the residual starting material.

An excellent paper to give you a better idea about some of the possibilities is Wolf and Lamb Reactions: Equilibrium and Kinetic Effectts in Multipolymer Systems, B.J. Cohen, M.A. Kraus and A. Patchornik, J. Am. Chem.. Soc. 103(25), 7620, (1981).

Insoluble reagents which are not polymers can also be classified as site isolation reagent:. an example would be activated manganese dioxide.

One can imagine the use of manganese dioxide with a strong base bound to a resin also combined with an epoxidation peracid bound to a second resin combined with semicarbazide adsorbed on silica gel.  This combination might be expected to convert an olefin to an epoxide using the peracid; the epoxide could be isomerised to an alllylic alcohol by the tethered strong hindered base; the allylic alcohol could be oxidized to an apha- beta unsaturated ketone by manganese dioxide and the ketone could be trapped and immobilized on the silica by the semicarbazide carbonyl derrivatizer.

I’m not saying this would work! It illustrates the concept.

A Potential Widely Applicable Solution for Resolving Chiral Bases

The problem of resolving enantiomers of chiral basic compounds does not have a general solution. There is no chiral acidic substance that quite dependably will form diastereomeric salts that can be separated at-scale synthetically usefully. 

There will probably never be a reagent that will work for resolving every enantiomeric pair but a solution might be closer than is commonly apparent.  TAPA which is (2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid has been available by an Organic Synthesis preparation since 1973. The compound was developed initially to resolve chiral polycyclic aromatic molecules with neither acidic nor basic functional groups. It works by forming diastereomeric charge-transfer complexes between the pi donor rings of the chiral polycyclic aromatic racemate and the pi acceptor, electron-deficient rings of the TABA reagent.

Subsequently, the enantiomeric TAPA reagents were used to resolve chiral antimalarial agents that had large hydrophobic amine groups that formed salts poorly. [F. Ivy Carroll, Bertold Berrang and C.P. Linn. Resolution of Antimalarial Agents via Complex formation with alpha-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid. J. Med. Chem.. 1978, 21(4) 326-330.]

When the structure of the enantiomers to be resolved has both a primary, secondary, or tertiary amine and a potential electron-donating ring there are two points of attachment between the enantiomers and the chiral resolving agent increasing the potential for success.  In the paper referenced above 5 different compounds were successfully resolved using this pair of (+)-TAPA and (-)-TAPA. No compounds are reported to have failed resolution.

Even when there is no polycyclic aromatic pi donor in the racemic basic material that you are trying to resolve, a solution may be possible if the amine is primary or secondary. The introduction of a benzylic protecting group that incorporates such a pi donor might provide a new compound that can be easily resolved. Removal of the benzylic group by hydrogenolysis for example would return the resolved material that is sought.

The Possible Use of Hexachlorocyclopentadiene to Purify Olefins

Compounds that contain double bonds often suffer from the presence of isomers in which the double bond is in a different location. These contaminants are usually very difficult to remove. Hexachlorocyclopentadiene is a reagent that reacts readily with a double bond that is not conjugated to any electron withdrawing group.  This is precisely the situation that is most likely to be difficult to separate. Hexachlorocyclopentadiene is reactive enough that it adds twice to naphthalene molecules once at each of the two double bonds in an unsubstituted ring. This use in fact is its best known application where it acts as a protecting group for an unsubstituted ring in a naphthalene.

 There is also a literature report that ordinary alkenes react at different rates with hexachlorocyclopentadiene. 1-Octene has an activation energy of 20 kcal and 4-methyl-1-cyclohexene has an activation energy of 24 kcal. These exemplify Diels-Alder reaction occuingr with unactivated alkenes. Although hexachlorocyclopentadiene is expensive when obtained from Aldrich, it is still probably available somewhere in bulk inexpensively. The disposal of the chemical must be handled carefully since it is an environmental toxin.

The adducts of this reactive dienophile are reported to be split back into their precursors by heating with phosphorus pentoxide and distilling the non-chlorinated adduct. This is an inconvenient, inefficient and damaging procedure that cannot promote widespread use. Using the adducts to remove an unwanted contaminant by reaction however would not have this disadvantage since the reversal of the reaction with an impurity would not need to be reversed.  An excess of the hexachlorocyclopentadiene could be used andwhen the reaction has proceeded to required extent as judged by in process analysis, the excess could be removed with maleic anhydride followed by mild base extraction of this adduct as sodium salt. This would leave the hexachlorocyclopentadiene adduct of the more reactive alkene impurity and the desired less reactive product.

The titration of a mixture of reactive alkene, hexachlorocyclopentadiene and adduct with bromine gives the residual amount of the olefin because neither reagent or the adduct react under ice temperature conditions.