Replacement process solvents

A recent Organic Process R&D editorial (thanks Chemjobber for pointing it out) publicizes Pfizer Process Group green solvent replacement chart that discourages chemists from using solvents that are either known to be toxic, dangerous to use on large scale or are expensive to dispose as waste. OPR&D makes it now a submission policy that if you used a problematic solvent in your work you have to demonstrate in your paper that you tried (and failed) to find more process-friendly alternatives. I think it is a sensible policy for a chemical industry process journal (and it probably makes the editors job of rejecting marginal manuscripts easier).

Also, Innocentive challenge was recently promising an award (up to 8k) to a winning proposal for replacing dipolar aprotic solvents like DMF, DMAc, NMP with less enviro-problematic alternatives.

I have few comments on the recommended solvent replacements in the table:

1) Acetonitrile is a perfectly good replacement of other dipolar aprotic solvents for things that dissolve in it, unfortunately MeCN dissolving power is quite poor. On the other hand, DMSO is famously bio-innocuous and it dissolves almost anything organic, and quite a few inorganic salts as well. But DMSO properties can complicate the workup, and DMSO can participate in quite a few unwanted sidereaction. I think overall DMSO is a pretty good media for alkylations that involve a reactive nucleophile. If the alkylating agent is highly reactive one might end up with S-alkylated DMSO-derived sideproducts although for many reactions this is not really a problem. Boiling DMSO has oxidizing properties and gives off Me2S funk so the reactions run in DMSO should not be heated above 140C. For acylations (where DMSO would interfere badly) an inexpensive eco-friendly solvent to try is 1,2-propylene carbonate, perhaps diluted with MeCN or DCM to cut down on this high-boiling solvent and to lower the viscosity. Propylene carbonate stability is quite remarkable – it tolerates alkali metals – but I would not heat it with alkoxides and reactive amines, the same limitation as with DMF and NMP. Another possibility for acylations is sulfolane-MeCN mixture. Adventurous eco-fanatic types may even go for triethylphosphate, another cheap degradable goo.

2) A suitable alternative for replacing DCM and DCE in many reactions (but not for AlCl3-promoted Friedel-Crafts) is trifluoromethylbenzene, bp. 102C.

3) For pyridine replacement the chart recommends NEt3 but I think N-methylmorpholine would be a closer surrogate/better alternative – NMM it is much less basic than NEt3 thus less prone to cause ketene-related dark impurities and racemizations during acylations, and it is a better solvent also. A strong fishy reek of NMM is a bit put-off though. If one so desires, Grignard reagents can be prepared in NMM.

4) One relatively underused process solvent is di-n-butyl ether. Its odor is annoying, the boiling point is quite high (142 C) and the dissolving power of Bu2O is not great but this solvent is cheap to buy and easy to dry. Room temperature lithiations with BuLi that require an etheral co-solvent might be a good pick for Bu2O (THF gets cleaved with BuLi at room temperature at appreciable rate, MTBE is pretty inefficient for solvating Li)

Fighting Pd colloids with salt

I have been running some debenzylations of a macromolecule with the Pearlman catalyst  in water. The hydrogenation often results in reaction mixtures with persistant dark colloids. I have seen this kind of problem before, with small molecule-hydrogenations on Pd/C though it was never quite as bad. I suppose this polymer loves to stabilize Pd nanoparticles in water.  Pre-activating the Pearlman catalyst with hydrogen prior the substrate addition does not help much.

I noticed that in this case 1) Celite and other brands of diatom-based filtration materials are ineffective for removing the dark colloids but filtration through a thick pad of charcoal actually works, to a degree, especially when combined with disposable plastic submicron Millipore filtration setup (pilfered from biologists);  filtration through charcoal tends to be slow and in some cases charcoal alone does not remove the colloids completely. 2) Saturating the hydrogenation reaction mix with salt before the filtration breaks the Pd colloids – they actually coalesce into a perfectly filterable precipitate and are removed  with the Pd-C catalyst.

I wonder if this high-salinity trick (in a polar solvent) could be employed in workup of other reactions suffering from product discoloration by colloids, i.e.  Ru-catalyzed periodate oxidations or olefin metathesis.

Medchem Immigrant in the Polymer Republic

Five months on – and there is no looking back. With potassium metal freshly cut, with the glassware, solvent and monomer lines pumped down overnight to 20 mTorr, ready or not, macromolecules, here I come.

Trehalose!

A remarkable molecule:  Hygroscopic, edible, stable and pleasantly-tasting natural sugar. While keeping foodstuff moist and producing a desirable mouth-feel, trehalose also masks greasy rancid off-flavors like no other food additive. Trehalose inhibits lipid autooxidation by interacting with the C=C bonds of fatty acids. Trehalose has also a stabilizing effect on denaturation-prone proteins. It is an effective cryoprotectant and anti-desiccant for living cells.

Trehalose is widely used as food additive in Japan. (It got classified by FDA recently as ‘generally recognized safe’  so expect trehalose-immortalized pastry snacks at gas stations soon). Two protein-based drugs co-formulated with trehalose are already on the market.

I would like to direct you to a minireview from Dr. Higashiama, a research team leader at the trehalose manufacturer Hayashibara Co. Some important practical applications are discussed in detail:

“In this application, we examined the suppressive effect of trehalose on human body odor. The typical odor of a senior layer (odor from seniors) increases with age, especially 55 years or older. This odor contains unsaturated aldehydes such as 2-nonenal and 2-octenal. These aldehydes are produced by the degradation of unsaturated fatty acid (palmitoleic acid) in aged people’s skin. The subjects (55 years or older) were selected from our company. After a shower, their body was sprayed with a 2 % trehalose solution. They put on new underwear after the spray. Twenty hours later, the unsaturated aldehydes were sampled from the used underwear shown in this system using DNPH-column. The trapped aldehydes were eluted from this column and were analyzed by gas chromatography. The results showed a decrease of about 70 % in odor from seniors due to the action of trehalose (Fig. 7). This result indicates that trehalose has a suppressive effect on the formation of the odor released by the seniors’ bodies. The same results came out with the oxidation of fatty acid. Therefore, the application of trehalose for cosmetic fields is expected.”

T. Higashiama: Pure and Applied Chemistry 74, 1263–1269

(Fig. 8):

A scent of fresh soil

Our lab has been smelling a lot like disturbed soil lately, due to my work with 2-ethylfenchol. The flavor and fragrance division of Aldrich is a good place to start when you need highly hindered tertiary alcohols. While many of the low-molecular weight tertiary alcohols are minty and camphor-like, Et-fenchol smells like dirt. Actually in the concentrated state it reeks similar to TBS-silanol, but stronger. In more diluted form though it has a clean smell of freshly dug-up moist earth –  the smell is persistant and very convincing; a colleague asked me if he could wear ethylfenchol on his shroud when he goes to a Halloween party dressed as a mummy.

Turns out, 2-ethylfenchol prepared from (+)-enantiomer of fenchone has been developed with a specific purpose: as a substitute for geosmin – the terpenoid metabolite produced by soil bacteria that makes soil smell earthy. The earthy note is desirable in some compositions, i.e. for pipe tobacco flavoring, and since geosmin is rather hard to make cheaply a semisynthetic substitute was found. (Water utility companies are less fond of geosmin; the odor threshold of geosmin is incredibly low. Together with 2-methylisoborneol – another dirty-smelling terpenoid from soil bacteria/fungi – geosmin lends awful taste to tap water).

Et-fenchol from Aldrich comes in kosher grade, with a large seal from rabbi Gershon Segal on the bottle:

A taste of their own medicine

 Credit: Jirí Slíva

I got an e-mail from a patent litigation attorney representing a major pharma company, a company that puts beautiful ads on TV almost every night and whose name rhymes with “Mergers and Massacres”. Turns out, they have a problem with one of their drugs: the drug is selling just over a billion a year and a key patent covering this drug is being challenged by two generic companies. And since I am on the patent (with ten other authors), the company lawyers were eager to prepare me in case I get subpoenaed by the other companies challenging the patent. They offered a free legal representation during the hearings and they proposed to pay me as a consultant (“at my usual rate”).

They mentioned that they are trying to piece together the exact timeline of the project – I suppose questions like who proposed/synthesized what and when are important to the defense. And they are having problems: no-one from the original team is currently employed with the company.

This does not surprise me. I was laid off like everyone else when our research site was closed. (Also, our chemistry director was forced out just before the site closure and I heard that the company has brought some heavy investigation down on him). In the end, only a handful of employees got re-hired by our company and moved to other research sites. I suppose tracking down the patent inventors and interviewing them is somewhat difficult now – and it is possible that not everyone wants to be interviewed…

I did not call the company patent lawyers as they asked me to but we had a cordial e-mail exchange and I shared some of the impressions and experiences that I had while being (briefly) a part of their company – from the time they acquired us until they shut us down. I also reminisced on the class-action lawsuit that my ex-colleagues brought against the company because the company tried to cut their severance payments after the layoff. (The class action suit was settled out of court when the company paid in full – about 2 years late.)

I also reached out to the two generic companies involved in this litigation and let them know about this approach from my former employer;  I offered to answer questions about the history of this drug discovery and I gave them names of the few key inventors on the patent who could perhaps assist them more than I can. Then I wrote back to the legal team of my former employer to inform them that I contacted the other two companies involved in the litigation. I explained that I do not want money but maybe they could re-evaluate how they are going to treat the R&D inventors in the future. You know, in case they need them again.