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.