QDIS Blog

I recently read the C&EN article reviewing chemistry highlights from 2006. It covers a lot of interesting stuff that happened last year but two items caught my attention. One of happenings they cover is Tamaflu which I’ve posted about many times before and the other is about a new organic catalyzed asymmetric reaction. Each by themselves is fairly impressive but I find it interesting that the author did not tie the two together!!

For those of you not familiar with Tamiflu, here is the structure.

And then here is the reaction that forms four sterocenters and three carbon-carbon bonds. It is asymmetric and catalyzed by a proline derivative. [Control of four stereocentres in a triple cascade organocatalytic reaction, Dieter Enders, et. al., Nature 441, 861 - 863 (15 Jun 2006)].

What is amazing to me is that the author of the C&EN review didn’t comment on how related these two items are. I did not read the Nature article and maybe it does mention the possibility of using this reaction for this specific compound. I’ve not sat down to analyze what would be needed and am not familiar enough with this reaction to know what groups it might tolerate without affecting the overall reaction, but it certainly is a fascinating idea.

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One of the omnipresent tasks in organic chemistry is how to work up a reaction. One of my pet peeves is the many articles that say something along the lines of “worked up in the usual manner” or “extracted with toluene” and no further information is given such as the amount or number of times the extraction was performed. It was interesting to me to see an article talking about the extraction process and how the extraction of not only the product, but also the original reaction solvent is often of immense import in downstream processing such as washing or crystallization.

Removal of Reaction Solvent by Extractive Workup: Survey of Water and Solvent Co-extraction in Various Systems (abstract) Delhaye, L., Ceccato, A., Jacobs, P., Kottgen, C., and Merschaert, A.
Org. Process Res. Dev., 11, 1, 160 - 164, 2007, 10.1021/op060154k

This article looks at a variety of reaction solvents; DMSO, DMF, NMP, DMAc, TMU, DMI, THF, 1,4-dioxane, diglyme, and acetonitrile and how they perform with extraction solvents such as toluene, EtOAc, iPrOAC, 1-chlorobtuane and heptane in aqueous solutions such as water and salt water.

The article is well wroth reading and noting for future use.

This is in the first issue of the journal for this year and is available to everyone. Typically for some ACS journals the first issue of the year is free and available to everyone.

Removal of Reaction Solvent by Extractive Workup: Survey of Water and Solvent Co-extraction in Various Systems (pdf) or alternative html

Here is the Supporting Info.

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One of the omnipresent tasks in organic chemistry is how to work up a reaction. One of my pet peeves is the many articles that say something along the lines of “worked up in the usual manner” or “extracted with toluene” and no further information is given such as the amount or number of times the extraction was performed. It was interesting to me to see an article talking about the extraction process and how the extraction of not only the product, but also the original reaction solvent is often of immense import in downstream processing such as washing or crystallization.

Removal of Reaction Solvent by Extractive Workup: Survey of Water and Solvent Co-extraction in Various Systems (abstract) Delhaye, L., Ceccato, A., Jacobs, P., Kottgen, C., and Merschaert, A.
Org. Process Res. Dev., 11, 1, 160 - 164, 2007, 10.1021/op060154k

This article looks at a variety of reaction solvents; DMSO, DMF, NMP, DMAc, TMU, DMI, THF, 1,4-dioxane, diglyme, and acetonitrile and how they perform with extraction solvents such as toluene, EtOAc, iPrOAC, 1-chlorobtuane and heptane in aqueous solutions such as water and salt water.

The article is well wroth reading and noting for future use.

This is in the first issue of the journal for this year and is available to everyone. Typically for some ACS journals the first issue of the year is free and available to everyone.

Removal of Reaction Solvent by Extractive Workup: Survey of Water and Solvent Co-extraction in Various Systems (pdf) or alternative html

Here is the Supporting Info.

Technorati Tags: extraction solvents, solvents

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I’ve written before about MeTHF and though I’d pass along some information I recently came across in the journal Org. Proc Res and Dev.

Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions (abstract)
Aycock, D.F. Org. Process Res. Dev., 11, 1, 156 - 159, 2007, 10.1021/op060155c

Luckily for most, this is in the first issue of the year and is avaiable to everyone. Typically, it is for subscribers only. Free full aticle link Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions (pdf) or an alternate html.

I should point out though that the article is by David F. Aycock who works for Penn Speciality Chemicals and is a primary supplier of MeTHF.

There are several factors that make it such an interesting solvent.

• Unlike THF, it is not completely water miscible and does not readily form emulsions or rag layers.
• Its water solubility is low, 4 g per 100 g water.
• Moderate boiling point of 65.7 °C.
• Available from readily renewable resources (2-furaldehyde from corncobs).
• Forms azetropes with several solvents including water (10.6% water).
• Three times more stable than THF to 5N HCl at 60 °C.
• About the sme tendency as THF to form peroxides.
• Works well for forming Grignard reagents. Can form much more concentrated solutions than is possible with THF.
• Is a suitable replacement for dichloromethane.
• Effective for extracting polar alcohols such as 2-propanol from water. Two extractions with equal volumes extracted 94% of 2-propanol from water. Only 68% was removed using toluene.

On the downside though, this solvent is significantly more expensive than THF. Penn makes the argument though that you don’t have to use an extraction solvent that you must use with THF or that you can make more concentrated solutions of Grignard and so therefore use less solvent.

It is a good article and well worth reading and noting for future use for all chemists.

You can also view other articles in this free issue of Org. Proc Res. & Dev.

Other Resources

Products”>Penn Specialty Chemical Inc. > Products MeTHF
Methyltetrahydrofuran: How to Recover and Dry MeTHF Batchwise (pdf)
Penn Specialty Chemicals Inc.
ChemExper - catalog of chemical suppliers, physical characteristics and search engine (methyltetrahydrofuran)

Technorati Tags: MeTHF, PennSpeciality Chemicals, 2-methyltetrahydrofuran

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Many articles in the chemical literature use the words “optimized” or optimal” conditions in the report. Most of these in my experience are NOT optimized but rather a set of conditions were investigated and the best results obtained are then used. Out of curiosity, I looked at articles published in the following American Chemical Society (ACS) journals:

• Journal of Organic Chemistry (JOC)
• Journal of the American Chemical Society (JACS)
• Organic Letters (OL)
• Organic Process Research and Development (OPRD)

I choose these four since they are the major organic journals from the ACS and I happen to have subscriptions to all of them. A search of these journals for “optimized” or optimal” in the title or abstract from Jan 2000 to June 2006 resulted in 1065 hits. Searching within those results for those articles containing the word “statistical” results in 144 articles that actually used design of experiments (DOE) to determine the optimal conditions. This means that only about 13.5% of those claiming to be optimal or optimized actually are. I’m sure that if this was expanded to other journals the results would most likely be even lower. This is because the journal OPRD tends to publish quite a few very good articles describing the use of designed experiments resulting in a bias to the high side. My best guess is that including more journals would give a lower percentage of around 8-10%. It should be obvious that the vast majority of those claiming to be optimal really aren’t. They are probably pretty good, but certainly can’t be said with confidence to be the best conditions.

In the normal practice, a variety of solvents are chosen and then the best one selected and this is used to further optimize the conditions such as base. This “one factor at a time” process is quite common but ignores the interaction between the solvent and other conditions such as concentration, temperature, catalyst, reagent (i.e. base), etc. Also, at the end of an “optimization” performed using one factor at a time, you still don’t know for sure if you have found the best conditions. You only know that this set of conditions of those studied gave better results than the other conditions (but not necessarily the best). If a designed experiment is used, then you can arrive at a model for the system and predict where in the experimental space the best reaction conditions are, even if that set of conditions were not part of the design (however, you should always check and make sure this predict is correct). The use of designed experiments allows for the development of mathematical models (typically a quadratic equation) to predict results within the space studied. You can also study as many results as are of interest.

One reason DOE has not been used extensively is that you typically have to change your system to fit a design from a book or article. More recently, computer generated designs have overcome some of this although my experience is that most compute generated deigns are not of the best quality. They typically are what are called D-optimal designs and these designs concentrate on giving the narrowest confidence limits on the b coefficients. This means they are good at finding out how important a certain factor is, but are not the best for predicting the results which is typically what is of interest in industry. Here is an equation for a hypothetical example of a system looking at temperature (T), concentration (C) and catalyst (K).

Result = b0 + (b1 x T) + (b2 x C) + (b3 x K) + (b4 x T x C) + (b5 x T x K) + (b6 x C x K) + (b7 x T^2) + (b8 x C^2) + (b9 x K^2)

A D-optimal design will give you the best value for each of the b’s. This is good in cases where you may be studying eight or ten factors and you want to know the critical process parameters; say the three most important. They do not necessarily give the best results for the prediction of the result.

I-optimal designs however, are generated such that the best possible prediction of the result is what is of interest. It may not be entirely obvious but these are indeed different. Sometimes they may be the same but that is not necessarily the case.

QD information Services offers you the chance to use I-optimal designs that are specific for your set of circumstances. If you want to study four solvents and concentration as well as only three temperatures then we can provide you with an I-optimal design for that. If you are interested in a customized experimental design, feel free to send me an email and we can discuss your specific needs. We also offer help in analyzing the results and finding the true optimal conditions.

Technorati Tags: design of experiments, process development

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One of the primary tools available to the process development chemist to simplify a reaction sequence is to run multiple steps without isolating and purifying the intermediates. This is commonly referred to as “telescoping” reactions. The reasons for telescoping are many; limiting contact with a potentially hazardous compound, reducing cycle times, and reducing pollution and emissions among others. Some concerns are finding the correct solvent to allow the reactions to proceed as well as ensuring no reduction in quality occurs (no new impurities or elevated levels of known impurities). There can be cases where a new impurity is generated but others are eliminated and the new impurity is easily removed.

The Eli Lilly process group recently published an example os using telescoping to reduce toxic and odorous emissions. The first two steps involve formation of a sulfur ylide and the formation of a cyclopropane ring. Initially the steps were in two different solvents (acetone and MeCN). The major concern here is the use and emission of Me2S.

After screening several solvents it was found that both reactions would take place in MeCN and that DBU was the best base of those studied. I do have some concerns about how this was carried out, but that’s a story for another post. They determined the solvent first, then the base, and finally the addition times. This ignores the possibility of interactions between base, solvent and additions times. I better way is to use a designed experiment to determine the correct combination. It could be that one of the other bases with another solvent might give a better result.

Using MeCN as solvent and DBU as the base with quick addition of both DBU and the cyclopentenone gave good results (58% yield).

Process Development of (1S,2S,5R,6S)-Spiro[bicyclo[3.1.0]hexane-2′,5′-dioxo-2,4′-imidazolidine]-6-carboxylic Acid, (R)–Methylbenzenemethanamine Salt (LSN344309) Org. Process Res. Dev. 2006, 10, 28–32

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Coming from the process development side of the pharmaceutical industry I’m always interested in being able to efficiently model a process from the small scale to the large scale. A recent paper describes the researchers experience with scaling the drying process from a 200 g scale in a rotary evaporator (yes, than can be used for drying solids as well as stripping solvent) to a 1000 kg scale in three different types of driers.

Modeling the Scale-Up of Contact Drying Processes: Org. Process Res. Dev., 10 (3), 409 -416, 2006.

It should be noted that the model is not universal; only 5 of the 8 systems investigated worked. It also should be pointed out that there is still quite a bit of unpredictability. If, during the evaporation, the material forms one large lump (not an uncommon occurrence) then the model doesn’t work. The two other cases that failed were also due to aggregation during the drying process. While this aggregation can be reduced by reducing the rotation speed, this also slows down the drying process and resulted in longer drying times.

While this paper outlines a useful approach, processes such as drying still depend very much on the product itself.

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Most chemists know that a solvent change can have a dramatic effect the course of a reaction but what is not commonly appreciated is that a change of solvent can dramatically reduce impurities formed in a reaction and make the subsequent purification much easier or allow it to be eliminated entirely. I recently came across an example of this sort of can be seen in the following article:

The Synthesis of a Novel Inhibitor of B-Raf Kinase (Org. Process Res. Dev. 2006, 10, 70–77)

The reaction of 7-hydroxyisoquinoline with (CF3SO2)2O in EtOAc–pyridine gave the triflate in moderate yield (48%) after an aqueous work-up and a thin-film vacuum distillation. Quite a bit of material is lost in the course of the distillation due to the use of ethylene glycol which was used as a lubricant and to solubilize pyridinium salts.

Changing the reaction solvent from EtOAc to t-BuOMe led to more efficient removal of the salts during the aqueous work-up, the use of less ethylene glycol which gave a higher yield (75-85%) as well as allowing the distillation to proceed at a lower temperature. All this from a simple change from EtOAc to t-BuOMe.

I’ll be honest, this wasn’t the reason this article first caught my eye. I read it because I noticed they used a Negishi coupling in their synthesis. I received my PhD from Purdue University under the supervision of Dr. Negishi and spent quite a bit of time working on this sort of coupling back in the late 80’s. I’m always pleased to see the words “Negishi coupling” and “uneventful” in the same sentence. It was interesting, although disturbing, to see some of the same problems we experienced back 20 years ago. This includes control of temperature for the Li halogen exchange and that the Pd catalyst nature is vital. It would have been interesting to look at other ligands. My experience is that trifurylphosphine instead of triphenylphosphine sometimes gives much better results. It would also be interesting to investigate using the Pd catalyst for the amination as well (Buchwald coupling) instead of dealing with the hydrogen evolution resulting from deprotonation of the amine with NaH and then coupling with the aryl chloride.

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I have posted a spreadsheet which will help in the initial evaluation of explosive hazards for chemicals. Here is the page where it is located.

This is from a paper by E. S. Shanley and G. A. Melhem of Arthur D. Little, Inc., entitled “The Oxygen Balance Criterion For Thermal Hazards Assessment“. Originally published in Process Safety Progress Volume 14, Issue 1 , Pages 29 - 31 Published Online: 17 Jun 2004

Here is the equation:
Oxygen balance = [1600 * (2x + (y/2) - z)] / M

Where:

M = molecular weight
x = number of carbon atoms
y = number of hydrogen atoms
z = number of oxygen atoms
(other heteroatoms are ignored)

If M (oxygen balance) is between -80 to +120 then the hazard potential is high
If M is +240 to +120 or -160 to -80 then the hazard potential is medium
If M is > +240 or is < -160 then the hazard potential is low.

An example: anisole C7H8O1 MW: 108.14

oxygen balance = [1600 * (2 * 7 + ( 8 / 2 ) - 1 ] / 108.14
oxygen balance = [1600 * ( 14 + 4 - 1 ) ] / 108.14
oxygen balance = [1600 * 17 ] / 108.14
oxygen balance = 27200 / 108.14
oxygen balance = + 252 therefore it isn’t a thermal hazard since it is > +240

The spreadsheet allows you to enter the molecule’s molecular weight and number of carbons, hydrogens and oxygens in it and the spreadsheet will then calculate the oxygen balance and color code the result. Below is a screenshot.

If the number is medium the result cell turns yellow; if it is high, the cell will turn red. This gives a visual feedback in addition to the number itself.

This is by no means a substitute for actual testing, but can give you a rough idea of the potential explosive hazard. The authors state that it is conceptually flawed and often dangerously misleading as a guide to energy release in general since it is based on stoichimetery. To fully answer such questions, you need to use thermochemical and kinetic considerations.

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In getting caught up on some of my literature reading, I came across an interesting article from the journal Organic Process Research and Development. Having spent my career as a development chemist, this journal is invaluable in keeping up to date with tricks and tips for large scale production. The following article was in the latest issue (Organic Process Research & Development 2006, 10, 163−164).

A Simple Modification to Prevent Side Reactions in Swern-Type Oxidations Using Py·SO3 Lijian Chen,* Steven Lee, Matt Renner, Qingping Tian, and Naresh Nayyar Chemical Research and Development, La Jolla Laboratories, Pfizer Inc.

The article describes using excess pyridine to convert the pyridine•sulfuric acid 1:1 salt which is present in commercial pyridine•sulfur trioxide to a 2:1 salt. This prevents unwanted side reactions from occurring, at least in this report. In this case they are oxidizing a primary alcohol to an aldehyde and then performing a Wittig reaction without isolating the aldehyde (a common approach in chemical development and production).

I just find it interesting that as widely used as the Swern oxidation is, this hasn’t been reported before. It is interesting to know that there are still “well-known reactions”, that actually aren’t. My usually reaction to being presented with a route containing a Swern oxidation is to ask what other oxidizing conditions have been tried. Unfortunately, at least early in the development process, nothing else was tried because the Swern oxidation worked so well.

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