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?

–

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. 

Undergrads were on spring break last week, so no lab last week.  This week, we performed the Jones oxidation of isoborneol to camphor.  The crude product was put in the bottom of a Hirsch funnel with a cold finger, and the product was purified by sublimation.  One of my favorite chemistry trivia facts is that the opposite of sublimation is deposition.  Now you know.

I must say, I am really, really disappointed with the way this week’s demo turned out.  Plan A was following a patent prep to immobilize Jones reagent on silica gel.  That actually worked really well.  No problems there.  I had a nice orange granular solid.  The next step was to pack it into 5″ pipets between glass wool and plain silica gel to create a tall, narrow column of Jones reagent.  That also worked really well.  I meant to take a picture of the setup before I dumped everything, but I was pretty down after it didn’t work and just poured it all into my chromium waste bottle.  Sorry.

Anyway, the plan was to ask if anyone came to lab drunk that day (no one admitted they did), then have someone volunteer to swish around some Listerine for a while.  Then attach a clean drinking straw to the pipet and blow.  See, Listerine is 21% alcohol, so there’d still be some ethanol vapor in the breath which should flow past the Jones reagent.  The Jones reagent will oxidize the ethanol to acetic acid and will itself be reduced.  The reduced chromium reagent is greenish brown.  With the pipet system, the orange color would slowly change over to green from the start to the finish.  The amount of ethanol in a person’s breath (and therefore the BAC) can be determined by seeing how far up the column the green color extends.  The more solid that is reduced to green, the more wasted the person.

I know there are several potential safety issues with this setup.  Chromium is toxic and shouldn’t be ingested or released into the environment.  The goal was to have only me handle the glass and only the student with clean hands touch the drinking straw – which was not ot be unwrapped until just before use.  When I was testing this, I don’t know what was going on, but I could get no air pressure through the pipet.  With breath not flowing through the pipet, there’s no chance of the Jones reagent being reduced, so no demo.

See, they really did used to use Jones reagent in breathalyzers.  They don’t anymore because chromium is toxic, and well, lots of things can reduce chromium… not just ethanol.  This leads to false positives.   Now they use a fuel cell for better results.  The best part of the Jones reagent story is that drunk people would blow through a solution of Jones reagent, which would reduce some of the chromium.  A UV/Vis detector could measure the absorption of the solution before and after the test.  The absorption is related to the amount of ethanol because the measured absorption (A) is equal to the product of the concentration of chromium (c), the path length of the cell (l), and a constant unique to chromium (ε).  A =εcl.  This relationship, ironically enough, is known as Beer’s law.  That’s right.  Beer’s law can be used to tell how drunk a person is.

Plan B was to have a row of test tubes with a solution of Jones reagent to which was added increasing amounts of ethanol.  This would gradually change the color from yellow to greenish.  A separate test tube with a solution of Jones reagent in lab would have an arbitrary amount of ethanol added to it.  It could be titrated against the standards to show the color change and determine the level of drunkenness.  Problem is the color change is very subtle in dilute solutions.  Too subtle to really see.  No demo again.

I won’t bore you with plan C, but suffice it to say – fail.

So finally, plan D.  Same as plan B, but with a surrogate for Jones reagent… and a surrogate for ethanol.  Basically none of the actual reagents, but would still give a color change.  I went with acid/base chemistry.  A row of test tubes was filled with an acidic solution of bromocresol green.  The acidic solution is yellow.  To each tube was added an increasing amount of sodium hydroxide so the color would gradually change to a deep blue.  The first test tube was yellow, then gradually orange, then muddy brown, then blue.  In fact, the series hit just about every color EXCEPT green (the image looks better.  Mine was not nearly so nice.  I was in a hurry).   Anyway, then an arbitrary amount of NaOH was added to a separate tube with an acidic solution of bromocresol green and titrated against the standard.

It wasn’t a great demo, but it looked like it was supposed to look.

Note that in the cyclic isomer of glucose – β-D-glucopyranose (left) – all 5 substituents on the pyran ring are in the low-energy equatorial position (actually, the lowest-energy conformation of glucose is α-D-glucopyranose, where one of the -OH substituents is in the axial position. It is stabilized by what is known as the anomeric effect)

To which Mitch commented:

In regards to the anomeric effect, no one else finds it strange that when there is no good stereoelectronic effect explanation all of a sudden hyperconjugation is the key?

First, a mea culpa.  For unsubstituted glucopyranose, the β isomer is the lowest-energy isomer, and the α isomer is disfavored at a ratio of about 64:36.  When the hydroxyl group at the acetal position is changed to a methoxy group, then the α isomer is the lowest-energy isomer at a ratio of about 67:33 – the selectivity reverses. (click images for larger throughout) (update: figure labels fixed)

Second, my PhD research relies heavily on the anomeric effect, and I often get this ‘I don’t understand the anomeric effect’ response from people.  They assume it’s all handwaving.  I’d like to explain the anomeric effect and hopefully clear up some of the confusion surrounding it.  Read more below the jump.

We remember from undergrad organic classes, that substituents on a cyclohexane ring prefer the equatorial position to relieve steric strain.  There is a corresponding ring-flipped chair in which the substituent is axial, and the energy barrier associated with this ring flip can be quantified.  For cyclohexanol, the equatorial position is favored at a ratio of about 9:1.

When an endocyclic heteroatom (typically oxygen, nitrogen, or sulfur) is introduced at the position adjacent to the hydroxy group, for the example of methoxypyran, the hydroxy substituent now prefers the axial orientation – in spite of the associated steric strain – at a ratio of about 4:1.  This trend is not limited to oxygen substituents.  Any electronegative element will prefer an axial position when a heteroatom is on the adjacent endocylic position.  For the fluoro-xylose derivative in the image, the fluorine prefers the axial position EVEN THOUGH all of the other substituents are also axial.

This phenomenon is known for acylic systems, too.  If you were asked to draw a Newman projection for pentane and dimethoxymethane, for pentane you would drawn the Newman projection where the two bulky substituents are antiperiplanar to each other to minimize steric interactions.  And you’d be right.  But for dimethoxymethane, the two bulky substituents are gauche to each other in the lowest-energy Newman projection.  As a hint to what’s going on, this puts a lone pair on oxygen antiperiplanar to the electronegative substituent.

So why is this happening?  There are two main explanations given, and they both work together to explain why the seemingly more sterically hindered conformation is the most stable.  On one hand, when the electronegative substituent is in an equatorial orientation, the local dipole moment of the substituent and the local dipole of the endocyclic heteroatom are pointing in relatively the same direction.  This alignment of dipoles leads to a large net dipole for the molecule.  However, when the electronegative substituent is axial, the local dipoles are more or less pointing away from each other.  This relief of a net dipole is stabilizing for the molecule.  This is a fine explanation, but I don’t think it fully accounts for all of the stabilization seen in these systems.

The other main explanation is a molecular orbital argument.  In short, whenever you can lower the energy of a system, the system is net more stable.  When the electronegative substituent is in an axial orientation, the C-X sigma* antibonding orbital is directly lined up with the axial lone pair of electrons on oxygen.  This allows for some delocalization of the lone pair of electrons into the sigma* antibonding orbital.  The electrons from the lone pair interact with the sigma* antibonding orbital in a stabilizing manner.  The elctron density is now spread over two atoms.  The delocalization of the electrons results in a stabilization of those electrons, and leads to a net stabilization of the molecule.

But why don’t all groups next to an endocyclic heteroatom prefer the axial orientation, you might ask?  Why wouldn’t a regular methyl group be stabilized in the same way?  There is a trend amond endocyclic and exocylic groups which rates the ability to donate or accept electrons.  A carbanion is among the best electron donors, and heteroatom lone pairs are pretty good donors, too.  Things like C-H sigma bonding electrons aren’t such good donors, but do delocalize to some extent (this is why teritary carbocations are more stable than methyl carbocations).  There is a similar trend for electron accepting groups.  An empty p orbital is among the best acceptors, and C-X sigma* antibonding orbitals are pretty good, too.  The reason for this is the relative energy of the donating and accepting orbitals.  Carbanions and heteroatom lone pairs are relatively higher in energy than C-H sigma bonding electrons, and p orbitals and C-X sigma* antibonding orbitals are relatively lower in energy than C-C sigma* antibonding orbtials.  When the donor and acceptor orbitals are closer in energy, the stabilization is more favorable.

I talked about this general phenomenon as it relates to hyperconjugation over on the forums, too, if you want to read more.

So to summarize, for a cyclic system, when an endocyclic atom (Y) has a lone pair of electrons, a neighboring electronegative substituent (X) prefers to reside in an axial orientation.  More generally for cyclic or acylic systems, when a heteroatom (Y) has a lone pair of electrons, an neighboring electronegative group prefers a gauche orientation – in spite of what sterics might dictate.  This allows for maximum overlap of the lone pair of electrons and the neighboring C-X sigma* antibonding orbital.

Update: Forgot to list my sources.  The two sources from which I pulled most of my analysis are:

• Juaristi, E.; Cuevas, G. The Anomeric Effect, CRC Press: BOca Raton, 1995.
• http://www.scripps.edu/chem/baran/images/grpmtgpdf/Krawczuk_Nov_05.pdf

On December 18, 2008, the Food and Drug Administration ruled the natural sweetener Truvia “generally safe” for use in foods and beverages. Truvia (trade name Rebiana) is comprised of a diterpene called steviol glycoside, which is isolated from the extracts of the leaves of the plant Stevia rebaudiana bertoni.  The herb Stevia—basically the leaves of the plant—has been available for years, so steviol glycoside is nothing new, per se.  Cargill Food and Ingredient Systems now markets Truvia as a singular, “fully-characterized product” (Stevia, by comparison is a witch’s brew of anywhere from 40 to 200 compounds).  More interesting data about Truvia can be found here.  As a result of the FDA’s ruling, Coca-Cola Company will soon launch a new line of reduced-calorie drinks with the most prominent being a new version of Sprite called Sprite Green (comes in a nifty aluminum can).

Stevia was purportedly discovered by Moises Santiago Bertoni in 1887 while exploring the forests of Paraguay—Stevia rebaudiana’s natural habitat (see: Econ. Bot. 1983, 37, 74-82).  Additionally, the plant had been identified in Korea, China and Japan (J. Med. Chem. 1981, 24, 1269–1271).  Word spread about the plant and eventually Stevia made its way to the US (courtesy of the Department of Agriculture) in 1918 due to the growing interest in its strong sweetness.  A wide array of physiological studies determined that the sweet sensation of Stevia derives from the presence the compound steviol glycoside.  Since then, several studies have been reported on its structure and function of steviol glycoside including stereochemical analysis (J. Am. Chem. Soc. 1963, 85, 2305–2309) and metabolic analyses (J. Agric. Food Chem. 2006, 54, 2794–2798).

In the spirit the Truvia saga, I figured that I’d cover its first total synthesis of steviol methyl ester, which Mori and co-workers first reported (Tetrahedron Lett. 1970, 11, 2411-2414).  Starting from the tricyclic methyl ester, Mori protected the aldehyde then installed ketone by way of a hydroboration-oxidation and ensuing Jones oxidation.  Deprotection of the dioxolane was accomplished using aqueous acid in acetone followed by tandem acid-catalyzed aldol addition to furnish the 1,3-ketol, which was converted to the 1,3-dione via second Jones oxidation.  Clemmenson reduction afforded the 1,2-ketol (I encourage you to push the arrows for that transformation), which was converted to the allylic alcohol by methylenation. 

As is the case with most “new” sweeteners, Stevia has been the subject of criticism over toxicological effects.  One study, conducted by John Pezzuto and co-workers at the University of Chicago, concluded that steviol is actually metagenic (PNAS 1985, 82, 2478-2482).  However, the asterisk to this scientific study—“steviol is mutagenic toward S. typhimurium strain TM677” and not human cells—should clearly be taken into consideration when weighing the toxicity of the supplement as a whole.  Just so we’re all on the same page, the “S” in “S. typhimurium” stands for salmonella—a bacterium. 

All in all, I think it’ll pretty interesting to watch more information about Truvia find its way into the public eye. 

I assume most readers will be familiar with the controversy about the two proposed structures of hexacyclinol, the original one (1) and a revised one (2), and about a total synthesis of 1 by James LaClair that was challenged by Rychnovsky and Porco on the basis of calculations and a synthesis of 2. The debate has been extensively covered in the blogosphere, e.g. in C&EN and by Derek Lowe.

Proposed structures of hexacyclinol

There is some new evidence now. An Italian group have simulated the 1H and 13C NMR spectra of both structures using DFT calculations (Org. Lett. ASAP). The calculated spectra seem to point to 2 as the correct structure. In addition, 1 cannot have the same spectra as 2 according to the calculations. The authors summarize: “The structure of hexacyclinol is confirmed to be 2. Furthermore, if 1 had been synthesized or was formed from an unforeseen reaction, its NMR spectra are sufficiently different from those of 2 as to guarantee their distinction.” This seems to exclude LaClair’s claim that structure 1, which is the target of his total synthesis, happens to have the same spectral data as 2. The authors of the paper are of course reluctant to draw the obvious conclusion.

Update: This piece of news has been covered in Derek Lowe’s blog. There has been quite a discussion, with James LaClair participating in person! It has also appeared in The Chem Blog.