Easy Amide and Hydrazide Hydrolysis and Alcoholysis

The paper referenced below has always intrigued me. The fact that a simple primary amide is reported to react readily while even a simple mono methyl amide does not suggests something remarkable is going on. Could it go through a diprotonated intermediate enabled by the local concentration of protons on the acid exchange resin? How would one work out answers? It is a heterogeneous reaction?

I reproduce my original blog article below.

Carboxylic Acid Hydrazides: A Carboxylic Acid Derivative that can be Purified by Phase Switching

The core Kilomentor strategy in chemical process development is to utilize isolated intermediates that can be phase switched for purification; commonly this can be done by extraction into an aqueous phase at one pH and then taken bake into an organic phase at a second pH.  Esters are a common functional group that cannot be switched in this way. Free carboxylic acids can but a free acid group can interfere with many reaction types. A carboxylic acid hydrazide is sufficiently basic (pKa ~3) http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf
 to form salts with mineral acids that would be water soluble and the hydrazide would not interfere in many transformation where a free carboxylic acid would. A problem would appear to be that the final form of the intermediate you might like to have may be the ester or free carboxylic group and it is not obvious that one can smoothly convert carboxylic acid hydrazides into esters or free acids. There is however a simple procedure available for doing this. 




Greenlee and Thorsett found that warming the acyl hydrazide with a fifteen fold excess by weight of Amberlyst 15 ion exchange resin under reflux in water, methanol, or ethanol gave the acid, methyl ester, or ethyl ester respectively in high yield. [William J. Greenlee , Eugene D. Thorsett  J. Org. Chem., 1981, 46 (26), pp 5351–5353] This methodology also worked to convert primary amides in the same way but secondary amides, even a simple N-methylamide was inert to the treatment. It is worth noting that peptide bonds in particular were not touched.

Although Amberlyst 15 acidic resin was used for most trials, other resins such as Amberlyst XN-1010 or Amberlite IR-120 were found to give even faster reactions.  Powdering the resin produced no increase in rate but did cause difficulties in the filtration of the resin when the reaction was complete.

A Molecule that gives Crystalline Solid Complexes with Simple Lewis Bases

This particular urea molecule seems likely to present interesting chemistry. From what I had seen up until my retirement about eight years ago chemists had not paid much attention to it. Of course a thorough up today literature search would be needed as well as a careful reading of Margaret Etter’s paper.

What particularly struck me was how this adducts were made by grinding together the components and that an adduct even formed with ethyl ether. What would happen with molecules with more than one Lewis base functions the question I had when I first blogged about the subject.

The origin blog article is reproduced below. 

Bis-N,N’-(3-Nitrophenyl)Urea can form Crystalline Solid Complexes with Simple Lewis Bases

If you have a compound that is at least as effective an electron pair donor as an aliphatic ether and that compound will not crystallize at all or will not produce good quality crystals, there is a possibility that it will crystallize as a molecular complex with a hydrogen bond acceptor. Is anything known about choosing such a complexing agent wisely?

 An answer is proposed in a paper by the late Margaret C. Etter,[Acct. Chem. Res. 1990, 23, 120-126].  This is not a paper that organic chemists or process chemists are likely to read.  The lead author was a crystallographer and solid-state chemist.  Bis-N,N’-(3-nitrophenyl)urea can produce solid stoichiometric compositions from substances as non-basic as aliphatic ethers.  It in turn can easily be synthesized from inexpensive commercial 3-nitroaniline. The α form of 1,3-Bis(3-nitrophenyl)urea is sufficiently poorly soluble to be crystallized in yellow prisms from acetic acid, benzene, chloroform, dichloromethane, 95% ethanol, ethanol,  or ethylene glycol. The compound precipitated when formed in benzene.

How could one use the urea compound to isolate a material that exists as an oil and will not crystallize? One could mix it with an approximately stoichiometric amount of the Bis(3-nitrophenyl) urea. One could mix the urea with your oil on a small scale by grinding them together in a mortar. By rubbing the materials together strongly one would form the co-crystals if formation was possible. Then dilute the solid with an antisolvent and filter the complex washing the complex with the antisolvent. Impurities that did not form the complex would be washed through leaving excess urea and urea-complex. To this add 300,000 MW polyethylene glycol and either grind together or heat in an antisolvent. According to   Acct. Chem. Res. 1990, 23, 120-126, the urea forms a non-stoichiometric complex with polyethylene glycol. This should liberate the first complexant which should be taken into the antisolvent. The urea and polyethylene glycol complex of the urea would be removed as insoluble solids. Only the components of the non-crystalline oil that formed the complex should be retained in the antisolvent.

Lewis Base/ Bis-N,N’-(3-Nitrophenyl)Urea Complex

+

Polyethylene glycol

↓

Lewis Base

+

Polyethylene glycol/ n. Bis-N,N’-(3-Nitrophenyl)Urea Complex

How this would work with a multifunctional molecule would need to be investigated.

Phthalic Anhydride Reaction or Isolation and Purification

Traces of an alcohol functionalized impurity in a  reaction mixture in which the desired product has no alcohol function may well be best removed by treatment with phthalic anhydride, mild hydrolysis of any excess anhydride, and aqueous removal of phthalic acid and the hemi-phthalate of the alcohol impurity by extraction with dilute aqueous ammonium hydroxide from an immiscible organic solvent containing the non-alcohol main product.

This could be cost effective because phthalic anhydride is cheap so the extra work-up cost would be little while the improvement in quality and overall recovery from crystallization of the non-alcohol could easily more than justify it.

The treatment might be useful after oxidation of an alcohol to a aldehyde or ketone; conversion of an alcohol to an ether; pinacol-pinacolone reaction; dehydration of an alcohol to an olefin.

The work could also explore whether some modification could be used to separate an alcohol which is the desired main product from a reaction mixture containing non-alcohol side products. Here at least  stoichiometric amount of phthalic anhydride would be necessary to convert all of the desired alcohol to the hemi-phthalate. 

The treatment might be useful after reduction of an aldehyde or ketone; to an alcohol; cleavage of an ether; hydroxylation of anything or hydration of an olefin; or hydrolysis of a halide.

Allophanate Derivatives for Isolation and/or Purification

Allophanate derivatives are likely superior to many other more common methods to isolate and purify substances that are formed in reaction where there arise several products.

For an example that might be tested in the laboratory, consider the hypothetical reduction of 4-methyl-3-penten-2-one, (mesityloxide), bp 129 C, by hydrogenation. There are three theoretically  possible products that are alcohols: 4-methyl-2-pentanol, bp 132 C, (ketone and double bond reduced); 4-methyl-4-penten-2-ol, bp 131.7 C, (only ketone reduced):  and 4-methyl-3-penten-2-ol,  bp 132 C, (ketone reduced and double bond isomerized). It is likely that reaction conditions can be found that lead to substantially one desired substance but such an enriched mixture still could not be separated based on boiling points. A solution that should be considered is the formation of the allophanate derivatives and the mixture’s recrystallization to get at the predominant compound’s allophanate in pure form, followed by hydrolysis back to the parent alcohol.

Another possible situation could arise in the practice of the Prins reaction. The Prins reaction is expected to produce a 1,3-diol from formaldehyde and an olefin. This is not necessarily a clean reaction. In fact, the infrequency of its application suggests that it may lead to multiple products. Formation of the bis-allophanates as a method to obtain a pure crystalline product seems to be worth investigating.

The literature suggests that allophanates are derivatives that can be expected to crystallize from even quite difficult mixtures.  For example the method was useful in the isolation and purification of various vitamins from natural sources. Fieser & Fieser in Organic Chemistry, the Third Edition, Reinhold Publishing Company, 1956 wrote,  “The isolation of two pure factors from wheat-germ oil concentrates in 1936 was simplified by the discovery of crystalline derivatives, allophanates, resulting from esterification of the factors with cyanic acid….. on hydrolysis of the derivatives, the two pure active factors were obtained as highly active pale yellow oils named alpha and beta tocopherol.”

Similarly the allophanate derivative was used by Windaus and coworkers in isolating Vitamin D₃ from an irradiation mixture. This is reported in Fieser & Fieser’s, Reagents for Organic Chemistry Vol. 1 pg. 171:

 “Treatment of the crude, oily mixture with isocyanic acid afforded directly a solid product easily purified by recrystallization from acetone and converted into pure vitamin by hydrolysis.” Vitamin D₃ has mp 82-84 C while the allophanate had mp 173-174 C, so one can see the inherent advantage. The co-products of the hydrolysis are conveniently totally water soluble!

Ideas for Undergraduate Organic Chemistry Research Projects

Wisely selecting an undergraduate research project for a student who wishes to concentrate in organic chemistry can motivate him or her to proceed to further studies in chemistry.  This is my goal in this blog.

It would be good if at the end  of the assigned period the student could see that (s)he had made a small but significant contribution to the ever growing body of science knowledge but this is not so easy. Research projects that end up bearing the words “an attempt….” or “the future steps required to complete this work….” do not provide the inspiration I have in mind; however, many prospective projects that would actually add to the overall body of knowledge either end up taking too much of a supervisor’s time, lead into unmanageable complexity, end up competing with experienced researchers, or are so narrowly focussed that any result is disappointingly inconsequential.

A problem particular to organic chemical synthesis is that too much of a project is taken up in the library working on route selection, for example, and too little time with experimentation in the laboratory. Since the whole object is to provide the student that initial feel for the hands-on research experience, this cannot lead to a successful project outcome.

Finally, if the student’s work can actually be worthy of publication; even if only online, the student will obtain a psychological boost that may be career defining.

How I Propose to Do It

Before retiring, most of my career was as an industrial pharmaceutical chemist. After retiring, I became a blog author. I authored the blog, Kilomentor, which aimed at teaching the fundamentals of organic chemistry process development and scale-up. While writing these articles I found out that there was very little published experimental work focussed on rugged isolation and purification methods that could be applied for preparative and large scale synthesis. Neither industrial nor academic researchers are interested in teaching the best methods for separation and purification of physically significant amounts of product. This is because industrial chemists don’t want to reveal more than a patent demands while academics don’t work in  areas where peer-reviewed journals won’t publish.

As a consequence, in many of my blog articles I note that experimental work needs to be done to actually show that such and such a technique works and will have the advantages that I maintain possible.

I think the studies that are needed will be largely experimental. They are limited; not likely to lead to overwhelming complexity; and less likely to require a supervisor’s repeated intervention.

Finally if the outcome is successful it can be published on-line and if it is not successful, mention in the comment  section of the applicable article at Kilomentor, preferably with a link to your work, will be valuable for my world-wide readership.