"Crystalline" CO - Saccharin's New Trick

Seems I'm posting an awful lot about artificial sweeteners these days!

This latest example, from the always entertaining and informative folks at Angewandte Chemie, employs our old friend N-formylsaccharin* as a carbon monoxide "equivalent" for Pd-catalyzed addition reactions:

Credit: Manabe Group | ACIEE

Quite a few benefits accrue: No pressure equipment. 'Medium' heat. Relatively low catalyst loading.  Cheap, off-shelf reagents. If they could figure out a slightly less exotic reductant, I'd use this all the time!

So, how does it work, anyway? The researchers confirm CO release by treating formylsaccharin with several bases and observing CO evolution.** The standard (boring) formylation model might be operative here - Pd oxidative addition, CO insertion, reductive cleavage (rinse, repeat). 

OR (more excitingly), the authors note that they detect a transient "acylsaccharin" by HRMS. This might imply that the formylsaccharin reacts directly with the palladated arene, or that the sodium saccharine byproduct plays a role in stabilizing / promoting reduction of the insertion intermediate.

Sweet.

*OK, so it's not saccharin itself, but pretty darn close. First developed by Cossy in 2011 for formylating amines.
**A great mechanism for those looking for cume questions!

'Green' Coca-Cola

Credit: Soda stream USA

I really enjoyed hearing Bob Mondello's NPR blurb about the debut of "Coke Life" in Argentina. Apparently, this soda contains stevia and table sugar, and sells in a plant plastic derived bottle. It's not as calorie-laden as traditional Coke, and bills itself as "green" (renewable). Thus, the new logo Coca-Cola rolled out: a green background, in place of the traditional red known the world over.

I have a secret: I've often wanted to peer behind the scenes as a Coca-Cola chemist. Think about all the different stuff you'd get to play with! Considering sweeteners alone, you have Diet Coke, Coca-Cola, Coke Zero, and now "Coke Life," which use aspartame, high-fructose corn syrup, sucralose, and stevia, respectively. Not just those, but dyes, vitamins, stabilizers, emulsifiers, preservatives, and much, much more. Best part? If you invent something exciting, you get to see it used by billions of people - more than your average pharmaceutical (and a much shorter development cycle!).

It's interesting to speculate on why certain artificial sweeteners didn't make the Coke cut. Certainly, lead acetate didn't - ask the ancient Romans why not. But diner table stand-by saccharin didn't, either. Perhaps too much bad press on its tenuous ties to cancer? And why not go back to using a truly "natural" sweetener, like sugar or honey? Cost plays a role here, as does consumer preference.*

I look forward to trying "Coke Life" myself. If anyone from Argentina reads this, let's work out some shipping arrangements.

*To me, HFCS tastes overwhelmingly cloying, but I've heard dedicated Coke drinkers describe saccharin as "metallic," aspartame as "sharp" or "bitter," and stevia as "too sweet" (Ha!). 

(More) CNN Chemophobia: What's a Chemical, Again?

(For more posts in this series, please click here and here...)

*PLEASE NOTE: The text of the original CNN article has changed!*

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Hey there, Cable News Network. We really have to stop meeting like this.

The latest snafu comes from CNN's Chart health blog courtesy of Twitter contact (and fellow blogger) Marc. The piece recaps an Opinion column written by Purdue neuroscientist Susan Swithers, which explores a strange and interesting phenomenon of artificial sweeteners: apparently, overconsumption of these compounds can fool the body into reacting as if sugar (glucose) were present, leading to unforeseen metabolic conditions.

The quibble comes a few paragraphs down, where the train falls off the track (emphasis mine):

"There are five FDA-approved artificial sweeteners: acesulfame potassium (Sunett, Sweet One), aspartame (Equal, NutraSweet), neotame, saccharin (SugarTwin, Sweet'N Low), and sucralose (Splenda).  

All of them are chemicals. “Saccharin was one of the first commercially-available artificially sweeteners, and it’s actually a derivative of tar,” says Swithers. 

Natural sweeteners, like Stevia - which has no calories and is 250 times sweeter than regular sugar - is not a chemical, but is still a processed extract of a natural plant, and increases your health risks similar to artificial sweeteners."

Wait, what did I just read? From a neuroscientist, no less! (perhaps a misquote?)

One of these comes from a plant.
But all of these things are chemicals

1. Stevia, a commercial FDA-approved non-nutritive sweetener, is most certainly a 'chemical.' I've included a handy graphic (right) in case anyone was confused.

2. That first statement in the second paragraph? Quite true; all five compounds listed certainly are chemicals, too! Kudos for that one.

3. Can I tell you how tired I am of fighting against the "everything from tar = bad!" mentality pervading modern-day society? Anyone dusting off that tired chestnut needs to rub their eyes (hard) and look around. They probably recorded the line using a polymer-based recorder (made from tar). On interview day, both folks probably wore synthetic fibers (made from tar) and sat on plastic chairs (made from tar). They may have quaffed their thirst from water bottles (made from tar) or eaten a Twinkie (made from tar). Perhaps they drove to work that day, using gas (made from tar) in their car (made from tar...well, and rocks), down a highway (made from tar) singing to a CD (made from tar) and passing farm stands selling fruits and vegetables (made from dirt, gases, and chemicals).

Until next time, CNN. And there will, of course, be a next time.

Update, 7/10/13: Fixed small error in steviol structure.
Update, 7/11/13: A commenter points out that stevia sweetness relies on glycosides; I'd originally drawn the aglycone above. Fixed, Thanks!

The Sweet Science

Hello, amine equivalent!
Source: Cumberland Packing Grp.

No, not boxing . . .chemistry!

From a fresh Org. Lett. ASAP, courtesy of the Amgen Process group, comes the 2-amination of some 3,5-disubstituted pyridine N-oxides. The group wants to add in an ammonia surrogate, but faces low conversions and poor regioselectivities (2- vs. 6-) with "standard" literature conditions (excess tert-butylamine, tosic anhydride). Substantial gains occur with a switch to Hunig's base and TsCl, but they need to find a bulky, electron-poor nitrogen source. Since we're potentially talking kilos here, price and availability become major considerations.

So what did the researchers choose as their "N" source? Saccharin. Yup, the artificial sweetener from the pink packets, used on process scale. Saccharin beat out many other "Gabriel-type" protected amines (phthalimide, Boc phosphoramidate, etc.), and you can't beat the price: about $5 / kilo. Under optimized conditions, the group saw yields from 21-97%, and product ratios of ~28:1. Better still, acidic hydrolysis (HCl, 80 degrees) frees up the 2-aminopyridine compounds, most of which are crystalline solids.

Pretty sweet synthesis.