Our lab uses a lot of (-)-sparteine in enantioselective aldol additions, so we tend to buy large bottles which last us a while.  As such, we haven’t had to order (-)-sparteine in a while.  But our bottle is getting low (read: there are a few hundred microliters left), and it’s time to order more.

But it’s all gone.

All of it.

No one sells (-)-sparteine anymore.  Acros.  Fisher.  Alfa Aesar.  VWI.  Strem.  TCI.  I’m sure I’m missing some, since I don’t actually do the ordering.  Our ordering guy called Aldrich specifically, and was able to order three 10 mL bottles (probably the last available in the world).

Well, today we get a letter from Sigma-Aldrich telling us… they’re canceling our order.  They’re not selling it anymore either.

What is going on, here?  Anyone know why the major (-)-sparteine shortage?  Is this all of a sudden or has this been happening gradually?  Is this related to the acetonitrile pinch, or is this something different?  Anyone got any black market (-)-sparteine they want to, er, not sell to us?

A recent article by Pradash et al. in Organic Process Research and Development illustrates the problems of polymorphism similarly: once the authors determined that there was another crystal form (‘Form A’) than the original (‘Form B’), they undertook a screening process (looking at varieties of solvent and crystallization techniques) to find other polymorphs. Interestingly, once they discovered a new polymorph (‘Form C’), they found that it was impossible to generate Form B in their laboratories. They selected Form C for its physical properties and moved it into the pilot plant; lo, they then found Form D. This new crystal form began predominating and “those seeded crystallization processes that consistently produced Forms A and C started to produce predominately Form D in the laboratory.” (Click on image to see pictures of the polymorphs and the structure itself.)

When I read these accounts, I am filled with admiration for pharmaceutical process chemists, the interesting science that they get to do and the vast reserves of patience and sangfroid they must have.  Chemistry (and manufacturing chemistry, especially!) is based on reproducibility and consistency; when issues arise, I suspect that there is a great deal of checking and double-checking to make sure that “this is really happening to us.” Also, I can’t help but wonder if those process chemists, when these issues are discovered, wonder if the laws of the physical universe are being temporarily suspended and some Loki-like diety is having its way with them.

Ok, so maybe they were originally talking about his math homework… but the joke’s still funny

Unlike The Periodic Table, Strategic Applications will not be a book you sit and read cover to cover.  Rather, Strategic Applications is an essential desktop reference in planning a synthetic route.  The most noticeable feature of the book upon first glance is the incredible breadth of detail given to each named reaction.  Each named reaction is given two complete (large) pages.  No more, no less.  The commentary begins with an Importance section giving a brief historical context as well as a general substrate scope and limitations.  As an example, the Suzuki Cross-Coupling begins:

In 1979, A. Suzuki and N. Miyaura reported the stereoselective synthesis of arylated (E)-alkenes by the reaction of 1-alkenylboranes with aryl halides in the presence of a palladium catalyst.  The palladium-catalyzed cross-coupling reaction between organoboron compounds and organic halides or triflates provides a powerful and general method for the formation of carbon-carbon bonds known as the Suzuki cross-coupling.  There are several advantages to this method: 1) mild reaction conditions; 2) commercial availability of many boronic acids; 3) the inorganic by-products are easily removed from the reaction mixture, making the reaction suitable for industrial processes; 4) boronic acids are environmentally safer and much less toxic than organo stannanes (see Stille coupling); 5) starting materials tolerate a wide variety of functional groups, and they are unaffected by water; 6) the coupling is generally stereo- and regioselective; and 7) sp3-hybridized alkyl boranes can also be coupled by the B-alkyl Suzuki-Miyaura cross-coupling.  some disadvantages are: 1) generally aryl halides react sluggishly; 2) by-products such as self-coupling products are formed because of solvent-dissolved oxygen; 3) coupling products of phosphine-bound aryls are often formed; and 4) since the reaction does not proceed in the absence of a base, side reactions such as racemization of optically active compounds or aldol condensations occur.

These introductions are followed by a general reaction scheme (click for larger):

Next is a detailed walk through of the detailed reaction mechanism.  As can be seen in the figure below, the most elegant aspect of this book is the careful use of color.  The reagents get their own colors, and new bonds formed are always black.  This is especially useful in reactions undergoing rearrangement, like the Ugi reaction:

The second page of each entry is dedicated to demonstrations of the title reaction in synthetic applications.  Several total syntheses are described with the step utilizing the named reaction highlighted.  I like this aspect.  It shows real-world applications and helps exemplify functional groups that tolerate the reaction conditions.

Each entry is extensively referenced, and even this is handled elegantly.  The references are split into three (sometimes four) categories: Seminal Publications, Reviews, Modifications and Improvements, and sometimes Theoretical Studies.  Several appendices at the back help your searching immensely.  The first lists all the named reactions in the book in chronological order of their discovery.  The next three appendices really help as they organize the reactions by reaction category (degradation, elimination, heterocycle formation…), reaction by affected functional group (from an alcohol, from a nitrile…), and reaction by target functional group (synthesis of epoxides, synthesis of oximes…)

This book is useful in many situations.  The other day the name of the Cannizaro reaction escaped me.  I couldn’t remember what it was called.  So I used the appendix for reaction by target functional group and looked up synthesis of carboxylic acids, and there it was!  I was writing a research proposal, and needed information on the Darzens glycidic ester condensation.  Thanks to the organization of the book, I was immediately directed to 4 reviews on the subject.  In my research, I was (am) having trouble with a directed ortho metalation reaction.  Forty reaction references appeared at my fingertips directing me to more information on the subject.  It’s also fun to browse through reactions I’ve never ever heard of (like the Hunsdiecker or Minisci Reactions).

I cannot stress enough how detailed and thorough and indispensable Strategic Applications is to the synthetic organic chemist.  When your book has a foreword by E. J. Corey and an introduction by K. C. Nicolaou, you know you’ve run into a winner.  Without question, this is the best named reaction book around.

No wonder the DrieRite’s always purple.

“Can Reaction Mechanisms Be Proven?” generated spirited responses from its reviewers. The reviews were approximately evenly divided, and all were of very high quality. The authors agreed with the editor’s proposal that the reviewers convert their reviews into rebuttals or affirmations of the authors’ position for publication along with the article, which has been revised based on the reviews. Most agreed to such a process and their comments appear here. We hope that publication of this paper and well-reasoned rebuttals such as those provided here will initiate a wide-ranging discussion. JCE will provide an online forum for further discussion of the issue. Our hope is that both faculty and students will contribute their opinions and ideas to this discussion. -JWM

Huh.  You don’t usually hear about that happening too often.  So now I had to read the article.  It’s pretty fascinating, and I encourage you to read it all.  I’ll summarize and give my thoughts below the jump

The paper starts out with a bit of philosophy: how do we know when we “know” something?  Note that textbooks routinely tell us  reaction mechanisms can never be proven.  That is, we always talk about the “proposed” mechanism, and we never leave out that adjective and refer in the definite to “the” mechanism.  The authors conclude this is ultimately a philosophical limitation to knowledge: inductive reasoning cannot actually prove the mechanism of a reaction.  Repeated observations may suggest a mechanism operates a certain way, but 100 observations does not guarantee the 101st observation will definitely be the same.

The only correct way to theorize and “prove” a reaction mechanism – according to this philosophy of knowledge – is to postulate all plausible mechanisms… then run experiments to refute as many as possible.  The last mechanism standing doesn’t even win, though, as it only claims the title of “proposed” mechanism.  This sort of Survivor: Mechanisms mentality implies that “all knowledge is negative.”  We cannot Know (capital K) the mechanism of a reaction, we can only Know every mechanism the reaction does not follow.

The authors criticize this theory of knowledge sometimes referred to as “strong inference.”  We as scientists might think about atoms and bonds and orbitals and electrons and trajectories and charges……. but these are all just pictorial metaphors and mental constructs of the physical attributes of molecules and molecular motion.  Thus, all mechanistic observations are made through these man-made representations.  Does a negative result really negate the hypothesis?  Or is there a flaw in our representation and interpretation of the data?  Furthermore, the “strong inference” model also downplays experiments supporting a proposed mechanism.  They do have merit and deserve to be supporting evidence for a mechanisms – not just a lack of evidence against a mechanism.

As to the history of the elucidation of a mechanism, early mechanistic studies certainly failed to offer conclusive proof of a mechanism – especially the structure and conformation of transition state species.  Steady-state kinetics rely on observations of reactants, intermediates and products.  With no direct observation of transition state species (which have lifetimes on the order of molecular vibrations, or dozens of femtoseconds), definitive conclusions about those species and their formation and subsequent degradation can only be speculative.

However, advances in technology are now allowing the ability to resolve molecular motion to the femtosecond scale.  The field of femtochemistry has allowed observation of some of these exceedingly short lived structures.  Zewail received the 1999 Nobel Prize in Chemistry for his work in femtochemistry utilizing ultra-short laser pulses.  His Nobel lecture is adapted into print here.

So what can we say about mechanisms?  Can we prove them?  The authors conclusion is ultimately a dogmatic one: reinforcing a negative view on the study of reactions and their mechanisms (all we can conclusively do is prove them false) potentially discourages aspiring students from utilizing all possible tools (and very powerful tools, at that) at their disposal.  But they also note that, philosophically speaking, “we can never “prove” a mechanism – or any other scientific theory – absolutely.” (emphasis added).

–

I think I tend to agree with reviewer David Lewis of Wisconsin-Eau Claire.  In his review, his answer to the title question is: it depends on what your definition of the word “proof” is.  It’s basically semantics.  Do we mean “proof” in the mathematical, Absolute Certainty sense of the word; or do we mean “proof” in the jurisprudence, Beyond a Reasonable Doubt sense of the word?  The answer to the title question changes depending on how you mean “proof.”  A sufficient body of support gleaned from a series of properly constructed experiments can serve to “prove” a proposed mechanism beyond a reasonable doubt … until such time as new knowledge or new technology allows for the construction of more and more thorough experiments to be carried out.

Two interesting case studies: the SN2 and the Mitsunobu reaction.  We all know how the SN2 reaction works, right?  Or do we?  The nucleophile should approach the electrophile from the back face, and – to preserve momentum – the leaving group should continue along the same trajectory as the incoming nucleophile, right?  Well, new evidence from the Wester and Hase labs suggests there might be more to it than originally thought.  Certain leaving groups were travelling significantly slower than expected by conservation of momentum.  The research team concludes that the nucleophile spins the electrophile 360 degC before undergoing SN2 addition.

The Mitsunobu reaction is a favorite quiz question for first year organic graduate students.  Next time you get asked the Mitsunobu mechanisms, tell your inquisitor, “it depends.”  Really.  The mechanism (click image for larger) changes depending on the nature of the azodicarboxylate, the nature of the phosphine, the pKa of the acidic proton, the phase of the moon, and the record of the Cleveland Indians.  Who’s to say the mechanism of the Mitsunobu reaciton has been “proven?”

I guess my final point would involve the conditions under which a reaction mechanism was “proven.”  A good mechanistic study will survey pH, concentration, electronic effects of the reactant molecules, etc.  But even still, all we can say is this is the postulated mechanism under these conditions.  Or, more melodramatically, this is the postulated mechanism on Earth. Remember, a reaction can theoretically proceed under any number of ionic, radical, diradical, and fragmentation pathways.  The energy surface for a reaction to occur is more like a mountain range.  The pathway requiring the lowest energy is the “accepted” mechanism.  But given sufficient energy and reaction conditions, other mechanistic pathways are attainable.  Given that the possibility for alternative mechanistic pathways exists to me says we cannot “prove” one mechanism as the mechanism.

In fact, this is kinda what the paper is talking about when it discusses eliminating all other possible mechanisms.  We can think of all sorts of crazy mechanisms to get to the product, and each of them will take a different path through our mountanous region of the energy surface.  We probe each mechanism to test its validity, and only the strongest mechanism surives.  This is why I liken this approach to Survivor.

Ya, know, I think we need a logo for Survivor: Mechanisms.  I’m no good with photoshop (or GIMP, for the open-sourced among us). But if you are, and you want to put together a logo for our Survivor island, you can email it to me, and I’ll post them here on the blog.  We’ll also need a name for our Survivor island.  I suggest Gibbs Free Pass (slogan: Minimal Energy Required).

Oh, and what do you think?  Can a mechanism be proven given our advances in technology?  Or is this all just a semantic triviality?

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I notice Sabbaitcal Epistles also covered this paper

I recently bought a 2009 re-issued copy of Pearl Jam’s first album “Ten,” originally released back in 1991.  Those who know me well are also aware of my interest in Pearl Jam; I enjoy collecting demos or live versions of their music.  Anyhow, their officially released re-issue contains a remixed version of their 1991 album and (in my opinion) parts of it sound distinctly different than the original mix.  For you music buffs out there in internet land, Brendan O’Brien—the original producer—dumped the supplemental reverb applied to the original tracks in this newer version.  As a result, the guitars and drums sound much cleaner and less wet (I recommend listening to both versions of “Why Go” or “Oceans” for a good example of the remixing).

Thinking about the whole concept of “re-issue” got me thinking about organic chemistry (big surprise).  How often do scientists report fantastically optimized results, table the idea, and then revisit it at a later date (to make vast improvements)?  Or better yet, how much “new” chemistry has derived from “re-issuing” processed developed in the late 19^th or early 20^th century?  My PI calls refers to this particular phenomenon as, “teaching an old dog new tricks.”  In writing my dissertation (an ongoing process) I had the pleasure of reading Lipshutz’s recent review about cuprate chemistry (Synlett 2009, 509-524; DOI: 10.1055/s-0028-1087923).  This personalized narrative discusses the Lipshutz group efforts and contributions to the field of copper(I) hydride chemistry. 

This article is of particular interest apart from discussing it at length in the ‘ol thesis.  A few months back, I had a conversation with a colleague of mine who claimed that since Stryker’s contributions, “conjugate reduction chemistry has (basically) fallen to the wayside.”  I recall laughing out loud at his remark.  “What about Lipshutz or Riant or even Buchwald,” I asked.  He claimed, with a sense of arrogance, that their work was “just a new twist on Stryker’s original work.”  Based off of this logic, if someone successfully synthesized Taxol from table sugar in three steps, would it be considered a new twist on Nicolau or Holton’s contributions?  Arrogance aside, this idea of “re-issuing” is a common phenomenon in research chemistry.  It’s done frequently, often to the tune of 10-20 additional printed publications (apart from the seminal contribution).  Perhaps, it’s these instances that call into question the process of “re-issuing” chemistry. 

That said, re-issued chemistry can result in significantly new discoveries and improvements on original methods.  Taking the conjugate reduction example, Stryker’s catalytic reactions, performed under a high pressure of H₂, were plagued with over-reduced products.  In switching the stoichiometric hydride source from hydrogen gas to PMHS, Lipshutz reported a vast improvement in reaction times and overall yields (Tetrahedron 2000, 56, 2779-2788; doi: 10.1016/S0040-4020(00)00132-0).  This change has spawned a whole new area of carbon-carbon bond formation, particularly in the field of reductive alkylation reactions. 

While I’m genuinely interested in the idea of inventing new and exciting reactions, the thought of tweaked processes resulting in “re-issued” chemistry is largely appealing (when done responsibly).  A prominent neutron chemist once told me that real chemistry lies in unexplored places.  “We want to be doing things that others aren’t,” he said.  I agree.  But on occasion, it’s necessary to explore the landscapes previously claimed by others for the betterment of the (scientific) community as a whole.

A number of people argue that the ability to get crystalline compounds is essential to be a good chemist, so recrystallization should always be done if possible. As a reward, you get EA-pure solids that are also easy to handle and may give you the occasional X-ray crystal structure (if you want to grow crystals). On the other hand, an additional effort is required: you need substantial amounts of material, which is no problem in a short synthesis, but can be a problem if it takes twenty steps to get to the product. If I have tediously made 50 milligrams of a material, I don’t really want to give ten away to be burned.

I wonder if elemental analysis is still a necessity today. In most cases you get all the information you need from NMR (identity and purity). What EA gives you is confirmation that your compound is pure as well as dry. Still, is it worth the trouble or just a waste of time? I suppose it all depends on the kind of research you’re doing. If you are “target-oriented”, as medicinal chemists like me are, I do not think it is worth it, as long as the final compounds being tested are pure. I suppose this is being sloppy, but I want to get a series of compounds in a reasonable amount of time. It might be a bit different in a total synthesis project, where the focus is on the pathway rather than the target compound per se.

On my flight into Salt Lake City, I was greeted to nasty turbulence, an overcast sky but a comfortable mid-50 degree temperature, which eventually turned to rain (there’s a chance of snow tonight). 

So, what happened today?

The Inorganic/Medicinal Version of Brown.  M. Frederick Hawthorne is slated to win the highly coveted ACS Priestley medal for his contributions to boron chemistry in SLC this week (March 24, 2009).  In addition to synthesizing polyhedral borane clusters such as B₁₂H₁₂^2- in the 1950’s, he is noted for his boron neutron capture therapy (BNCT)—a promising technique in the war on cancer (see: J. Am. Chem. Soc. 2007, 129, 6507-6512).  I realize this isn’t really news per se since C&EN covered it last June, but some of you might have missed it.

Smith’s Dithiane Chemistry.  I caught most of Amos Smith’s talk about his lab’s recent efforts in the realm of dithiane transformations (you should be thinking “umpolong”).  He did a nice presentation on multicomponent anion relay chemistry (“ARC”; for example see: J. Am. Chem. Soc. 2006, 128, 12368-12369 and Angew. Chem. Int. Ed.  2008, 47, 7082-7086) while making a cute comment that the resultant “protected” alcohols are easily removed with Philadelphia tap water.  For those not familiar, the Smith lab has been applying hybrid umpolong/Brook rearrangement chemistry to synthesize cool “proof-of-concept” natural product-like molecules.  Smith mentioned that this type of work has caught Jeff Johnson’s attention (hence the umpolong connection) evidenced by a fairly recent publication about the synthesis of zaragozic acid C (J. Am. Chem. Soc. 2008, 130, 17281-17283).  I had to leave the talk a bit early, but from my vantage point I noticed a lot of male chemists slowly starting to assemble for M. Christina White’s talk.  I was truly sorry that I missed it.  Oh, in case you were wondering, I did not notice her trademark ostentatious belt buckle.

CAS and Nanotechnology.  In the few hours I’ve been at the ACS conference, I’ve noticed that there’s an awful lot of material (no pun intended) on nanotechnology.  While nanotechnology touches areas of pharma, materials and even the molecular automotive industry, the issue of classification is making its way through the chemical community.  Roger Schenck (of CAS) did a fine presentation on the issue from Chemical Abstracts Service’s vantage point.  CAS currently catalogs 80 sections of chemistry (#1 is pharmacology), and, according to Schenck, CAS is not planning on adding #81 (which would be nanotechnology) anytime soon. It seems that the issue will be tabled for a bit longer while the field continues to grow/evolve.  For you history buffs out there, Schenck contends that nanotechnology probably began with Kroto’s C₆₀ discovery (Nature 1985, 318, 162-163). Interesting tidbit: Kroto even mentioned that he’d “prefer to let this issue of nomenclature be settled by the consensus.” 

Alright, I’m off to the expo social event.  See you tomorrow.