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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Sodium Hydride As Oxidant, Again? | Main | Synthetic Chemistry: All Mined Out? »

September 21, 2010

Want To Make an Amide? Have I Got Good News For You!

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Posted by Derek

Y'know, this is what I call an incremental improvement in the synthetic repetoire. I noticed this new paper in Tetrahedron Letters by its title, and read the whole thing just to make sure that I wasn't missing something.

Yep, that's right: someone has come up with a new way to form amides by reacting acid chlorides and amines. "But hold on," you say, "I thought that acid chlorides and amines form amides like an unstoppable juggernaut, which grinds to a halt only when enough HCl is given off to take the remaining amine out of contention". Well, you'd be right about that: but that's because you didn't think of using samarium metal as an acid scavenger.

Because that's what it seems to be here. The authors report that you have to pretty much use a full equivalent of samarium to get the high yields - control experiments with only 1/3 equivalent didn't work so well. What I wish they'd done is run the freaking control experiments with triethylamine. Or Hünig's base. Or pyridine. Or potassium carbonate, or aqueous 0.1N NaOH, or resin-bound nanocrystalline cesium complexes prepared in ionic liquids through renewable green chemistry whatchamacallits - in fact, with damn near anything else except stoichiometric metallic samarium, of all things. Well, OK: zinc and indium didn't work. I stand corrected. Give these folks another four or five Tet Lett papers, and they'll work their way back to baking soda. Only it'll be samarium bicarbonate, with any luck.

Perhaps I'm being unfair here. But really, amide formation is not a problem that is crying out for a new solution. It's really very, very, well worked out, and the number of options available for the experimentalist are nearly beyond counting. But now there's samarium metal. So if you're looking for the most expensive way you can think of to react an acid chloride with an amine, one that will make your labmates question your sanity and a reaction that will probably be a separate item all on its own come your next annual performance review, then go to it.

Oh, and one more thing: if you bother to read the experimental section, which apparently no one did, the procedure is titled: "General procedure for the homocoupling of terminal alkynes". Wrong samarium reaction, guys.

Comments (66) + TrackBacks (0) | Category: Chemical News | The Scientific Literature


COMMENTS

1. FMC on September 21, 2010 8:11 AM writes...

Good Lord !!!

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2. fungus on September 21, 2010 8:15 AM writes...

Someone remind me what the cost of an institutional subscription to Tet Lett is again?

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3. Any on September 21, 2010 8:18 AM writes...

LOL!!!

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4. barry on September 21, 2010 8:26 AM writes...

Wait for part 2 in the series: "Mild and Facile Method for the Synthesis of Samarium Chloride"

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5. processchemist on September 21, 2010 8:29 AM writes...

Part 3: "Samarium triflate, an excellent lewis acid in glycosidations"...

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6. Hap on September 21, 2010 8:31 AM writes...

I wonder how desperate you'd have to be to perform an amidation in your total synthesis to pull this method out, and whether your advisor would blink when you told him.

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7. Dr. Smalls on September 21, 2010 8:45 AM writes...

Let us not forget how many papers there are with new, catalytic methods for introducing a BOC group....

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8. john on September 21, 2010 8:57 AM writes...

when publication is your measure of success as an academic instead of innovation you get this crap.

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9. David P on September 21, 2010 9:22 AM writes...

I think I will add samarium to all my reactions from now on.

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10. processchemist on September 21, 2010 9:30 AM writes...

Part 3: "Samarium triflate, an excellent lewis acid in glycosidations"...

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11. Ugh on September 21, 2010 9:32 AM writes...

Samarium chips: $72.30/10 g

DMAP: $114.00/100g

Perhaps samarium is dirt-cheap in China. Heck, it will probably find its way into some folk remedy. Pretty soon, the Tet Lett preparative methods will call for a catalytic amount of some pulverized dessicated organ from an endangered animal.

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12. John Spevacek on September 21, 2010 9:35 AM writes...

What a life saver! Now I can polymerize polyamides. I'm going to call my new plastic "Nylon"!

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13. HelicalZz on September 21, 2010 10:06 AM writes...

Are you sure you read the paper right. Maybe they were just working in Samaria and using metal containers?

: )

And please, don't insult our intelligence. I don't doubt that many here could come up with far more expensive ways to react an acid chloride with an amine if they put their minds to it.

Zz

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14. Wavefunction on September 21, 2010 10:14 AM writes...

Maybe one of the authors is an amateur prospector and was lucky enough to strike a vein of samarium-containing ore. Something about everything looking like a nail when you have a hammer comes to mind...

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15. Indy on September 21, 2010 10:17 AM writes...

"...amide formation is not a problem that is crying out for a new solution."

This is one of the problems in current organic chemistry. Too many articles about using "solvent-free", a new obscure catalyst, a bizarre new additional component to well established reactions that, unless such new protocol is for real large scale/process chemistry reactions, it is all noise, a waste of publication space, and certainly a waste of time since no one will be running back to the lab to test or use such "new" reaction conditions.

New research and publishers/journals should focus on (and borrowing Derek's words) problems that really cry out for new solutions.

It seems that science is going at times into the ridiculous when articles like this one reach publication status.

My 2 cents.

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16. RB Woodweird on September 21, 2010 10:17 AM writes...

You know,maybe we should just stop making fun of academics who publish papers of apparently little or no utility to us. The PIs are under pressure to publish; the graduate students are under pressure to publish. Who applies the pressure? Us, that's who. The existing system, of which we are all a (mostly) compliant part. Let's rise up and overthrow the existing paradigm and these useless papers might stop. (Insert hysterical laughter here.)

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17. HelicalZz on September 21, 2010 10:19 AM writes...

In fact, this blog now has me curious as to whether I can effectively scavenge HCl created in amide formation reactions with high energy particle bombardment. Now if I can just get time in the Hadron collider to test this hypothesis ... (wait, let me write the grant first).

Zz

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18. Rock on September 21, 2010 10:22 AM writes...

Great Derek,
Now you just helped to make this paper one of TL's 'most downloaded'....

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19. InfMP on September 21, 2010 10:28 AM writes...

BURN.

Tetrahedron Lett. continues to SUCK.

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20. RM on September 21, 2010 10:39 AM writes...

Someone remind me what the cost of an institutional subscription to Tet Lett is again?

Your sanity.

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21. anchor on September 21, 2010 10:58 AM writes...

May the authors should check out "Nano Sm". Hmm..

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22. Marcus on September 21, 2010 11:13 AM writes...

Actually, I believe the same reaction could be done under much milder conditions, with catalytic amout of peanut butter- That should be publishable in Science!

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23. p on September 21, 2010 11:21 AM writes...

Of course, I suspect that there must be minute traces of Palladium in their Samarium.

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24. moleculartist on September 21, 2010 11:34 AM writes...

@ RB Woodweird: Right on the money. No one in academia or industry seems to have any interest in your contributions, knowledge, or problem solving abilities. They want to see people out of top schools with a bunch of papers, because if you don't have a bunch of publications you must be either lazy or an idiot or both. Even the big groups at prestigious universities are guilty of these shenanigans, paper after paper on new ligands for Pd couplings, incremental improvements at best.

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25. Greg Hlatky on September 21, 2010 11:50 AM writes...

You've heard of the Iron Age and the Bronze Age? We're now in the Samarium Age.

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26. nitrosonium on September 21, 2010 11:54 AM writes...

everyone knows the easiest way to make amides from amines and activated esters/acyl halides is nanoencapsulated unicorn dreams.

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27. Bob on September 21, 2010 11:57 AM writes...

This thread is solid gold! [Nanoparticulate of course]

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28. European Chemist on September 21, 2010 12:06 PM writes...

@RBW and moleculartist

Spot on. When we check out a new kid on the block who's started his career some 3 or 4 years ago, what's the first thing we do on his group's webpage? Click the "publications" tab and count them. Then maybe count how many of those are in JACS or ACIE.

This would give rise to much more of a discussion than is possible in a comment. On the one hand, you have to acknowledge that academia exists precisely to work on things which nobody cares about. That is, apart from the PI. Because if you deprive science of that, the words "fundamental research" cease to exist and I can assure you that we will be much poorer. On the other hand, the "tell-me-how-many-papers-you-got-and-your-h-factor" trend means that PI's that have the creativity and choice among many ideas for projects will ditch those whose logical conclusion would lead only to a second-tier paper, versus something which (if successful) can be published under some buzzword in one of the top journals. And that's pure evil.

Permalink to Comment

29. AlChemist on September 21, 2010 12:12 PM writes...

Reaction:14 lanthanides with 12 different solvents at one paper per combo Yield: One research institute with gov funding

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30. DCRogers on September 21, 2010 12:43 PM writes...

Damn, looks like I picked a bad month to short Samarium miners...

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31. Anon on September 21, 2010 12:59 PM writes...

Even funnier--google some of the first lines of the paper and see what pops up. It appears that others have a similar writing style, so to speak.

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32. milkshake on September 21, 2010 1:08 PM writes...

There is a powerful and mild protocol for coupling aminoacid-derived acylchloride substrates with very desactivated aminos (EWG-substituted and hindered at the same time). That protocol uses acyl chloride with 3 equivs of AgCN as a promoter and DMEU or DMAc as a solvent. I only mention it because it saved my reputation, twice, after everything else had failed.

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33. baychemist on September 21, 2010 2:27 PM writes...

Are we wasting our time here?
Milkshake has the point though.

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34. Sili on September 21, 2010 2:28 PM writes...

Maybe one of the authors is an amateur prospector and was lucky enough to strike a vein of samarium-containing ore. Something about everything looking like a nail when you have a hammer comes to mind...
My late supervisor once said something passing about exchanging an envelope full of cash for a chunk of Rhenium in an airport shortly after the fall of the USSR.

Apropos of nothing.

My flabber is pretty gasted that anyone would do this. It soundsl like a stuuuupid* student doing something very very wrong. But what completely bowls me over is that someone thought it was a good idea to tell the whole world that they have such utter morons* working in their lab.

*i.e. stupider and clumsier than me in the lab.

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35. xfz on September 21, 2010 3:30 PM writes...

I am not defending the authors of this particular publication. It is published in Tetrahedron Lett., and I believe most of papers published there are “incremental improvements at best”, so you need to lower your expectations.

I am assuming that most of the readship of this blog are scientists, so why don’t you ask yourself this question: among the scientific papers you have published so far, how many of them are (a) real breakthrough; (b) innovative; (c) incremental improvements at best or (d) crappy?

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36. Dutchie on September 21, 2010 3:45 PM writes...

I didn't know about Samarium till today, I'm not sure if I'm better off now.

And yes I have a degree in chemistry, probably missed the day that discusses element Sm

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37. mad on September 21, 2010 3:54 PM writes...

Is this an obvious reaction that need not have been published because its essentially textbook or is it just a low impact paper? From the comments it seems most feel there is no current practical application for this work but its otherwise new. Are people scoffing at this because it doest fit their pre-defined paradigm; is there truly no conceivable future application derivable from this knowledge?

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38. Mark on September 21, 2010 4:00 PM writes...

I agree with Milkshake. The years I spent in process chemistry has taught me that even the most "trivial" transformation don't work every time. I've beat my head against a wall trying to get esterifications, amide couplings and enol alkylations to work well.

Sometimes it's the most stupid looking research that saves your ass.

These types of papers might not be groundbreaking, but they aren't useless either.

Mark

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39. Anonymous on September 21, 2010 4:11 PM writes...

Actually I think the amide bond formation is far from a done deal, especially if you are a process chemist. We still don't have a super-environmentally benign method if you think about it.

However, I'm sure this paper deserves the mockery that it is receiving. Stoichiometric samarium ain't the answer.

But really, despite all our expertise and knowledge, there are very few reactions that couldn't be improved upon.

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40. tedthechemist on September 21, 2010 4:13 PM writes...

This is just another example of terrible editorial policy (publish any old twaddle) and incompetent peer review.It's not he first -look at Tet Lett, 1998, 4103 - exactly the same, but Zn used. These jokers claim that leaving out the zinc results in NO REACTION AT ALL - acid chloride + amine in toluene-I don't think so...what on earth were the referee's playing at?

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41. Nic K on September 21, 2010 4:29 PM writes...

Hello Milkshake,

Off-topic I know, but do you have a reference for your method? I'm currently faced with just that problem (and no, I'm not going to try samarium...)

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42. Katherine on September 21, 2010 4:42 PM writes...

mad, I'm no chemist, but as far as I can tell it's a like a chocolate chip cookie recipe that recommends baking them for 8 minutes at 350 degrees inside a metal box suspended over a bonfire made of dollar bills. Not exactly an addition to the corpus of human knowledge.

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43. Kevin on September 21, 2010 6:31 PM writes...

Probably the copper impurities doing the reaction...

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44. @Nic K on September 21, 2010 7:48 PM writes...

I'm not Milkshake, but OMG my coworkers have used AgCN in peptide synthesis before. Apparently formal acylium ions are hella reactive. Here are some references:

J. Org. Chem. 2003, 68, 1843-1851.

Indian J. Chem. 1998, 37B, 1109-1113.

Bull. Chem. Soc. Jpn. 1976, 49, 2335-2336.

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45. Anonymous on September 21, 2010 7:59 PM writes...

Just goes to show you...the days of discovering new reactions (I mean new reactions: ie: Diels-Alder, Wittig etc...) are long gone. Kind of like the depletion of low lying fruit in the drug discovery tree. We are going to see more and more papers of increasingly less importance as our field progresses. It's not our falt...we've just hit the ceiling. Coupled with that you have individuals trying to survive based on publication. It's a numbers game. What we need are new ways of thinking outside the box. The box is already full...a Call for out of the box papers LOL!

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46. Schmerck on September 21, 2010 8:55 PM writes...

TL peer reviewed?

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47. anon on September 21, 2010 9:36 PM writes...

This reminds me of all those paper which describe the amazing ability of Pd(OAc)2 to act as a very expensive Lewis acid.

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48. ProudPeptideChemist on September 21, 2010 9:46 PM writes...

In agreement with several statements above, I don't believe that the esteemed Dr. Lowe should dismiss amidation chemistry as a depleted mine. The all-purpose amidation enzyme has yet to be engineered, moreover there are few, if any, amidation methods that are mild, economical, and enviromentally friendly. Why not take shots at the aldol, Diels-Alder, Suzuki, or any other COMMONPLACE yet ESSENTIAL reactions? Anyway, my two cents regarding Tet Lett: Older editions tended to be more reliable, including the ones written in German and French.

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49. Mat Todd on September 21, 2010 9:49 PM writes...

Pressure to publish + bad peer review = papers like this. Peer review on the web like this after publication - much better.

While amide bond formation is easy, many methods suck, surely? Remember the paper from several pharma companies in Green Chem in 2007? (DOI: 10.1039/b703488c) 3rd page, Table 1 "Reactions companies use now but would strongly prefer better reagents" - top entry "Amide formation avoiding poor atom economy reagents". Not saying Sm fits the bill, clearly, but anyone who's done amide couplings (here meaning peptide couplings) knows how crappy those reactions can be.

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50. eugene on September 22, 2010 2:01 AM writes...

"We still don't have a super-environmentally benign method if you think about it"

The new amidation from Milstein involving alcohols and amines is benign. It can work in refuluxing toluene and the only byproduct is hydrogen. However, it's not mild (refluxing toluene) and it destroys the hell out of other functional groups (secondary alcohols) if they are there. Looking at the catalyst, I don't have many ideas on how to modify it in order to change this outcome.

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51. processchemist on September 22, 2010 2:12 AM writes...

@49

yes, amide formation (and acilations, and suzuki couplings) can be crappy, specially if you're looking for high yelds and scalable isolation of the product. But I can't count the already available methods.
The main problem of organic synthesis is that is now perceived as a huge collection of recipes. If a recipe is not working, the standard behaviour is to shift to another one without any consideration about why it's not working and what's really required to make the reaction work.
Once upon a time academia was not simply reporting a new recipe: it was expected to tell or demonstrate why and how the reported synthesis was working.

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52. Nick K on September 22, 2010 2:46 AM writes...

Anonymous poster @ 44: Many thanks for the references, much appreciated.

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53. Mat Todd on September 22, 2010 5:14 AM writes...

@51 - this is true.

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54. Jos Smoss on September 22, 2010 6:19 AM writes...

@ 40. tedthechemist

These guys, Reddy and Yadav have a history of taking a simple process; add metal (zink, indium, ...), and claim superior yields in a Tet. Lett. publication. They report some really nice things in pyrrole chemistry, and I have never been able to reproduce any of them. (eg Tet. Lett., 2002, 8133). For years I have suspected some kind of fraud here, so I am glad someone else in the world noticed their crappy papers.

The best thing of this paper is their claim that the zinc can be reused... Where does the HCl go to? Zinc chloride? Sure enough, but how the hell how do they recover their zinc?

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55. Dave UK on September 22, 2010 7:31 AM writes...

There are things you publish and those that you don't, as a PhD student I worked my way through the cupboard of Lewis acids to no avail and then on a Friday afternoon decided to use a well-known brand of Cola. Reaction worked a treat, shame about the next step though. Did we publish? Don't be silly of course not, there are somethings that the rest of humanity doesn't need to be exposed to, besides I didn't want to spend the next few months determining whether Fanta or Sprite was a better catalyst than cola or whether the Diet ranges impoved things, though if someone is trying to think of a subject for a project student....

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56. noname on September 22, 2010 7:48 AM writes...

I'm embarassed to find myself defending this paper, but here is the scenario that I speculate led to this research:

1) College dean or some other academic bureaucrat attends a Communist Party meeting in which government officials celebrate China's emerging monopoly on rare earth ores. (see recent article in CEN)

2) As a patriotic duty, college dean urges chemistry department to find new uses for rare earth metals. Grant funding is guaranteed for researchers who can further the national interest by finding applications of this collective resource.

3) Poor schmuck in the chem department says to himself "You want a use for rare earths? I'll give you a use for rare earths!" And comes up with the research we are all mocking.

4) College dean says "That's great, but it has to be published in a Western journal to show the world the value of our national resource." Researcher says, "Get this POS published in a Western journal? Well there's only one option...TL!" (I say this as a frequent referee for TL; I try my best, honest!).

5) The rest is history. Science driven by politics and ignorance. It happens in the US, too.

Permalink to Comment

57. European Chemist on September 22, 2010 8:51 AM writes...

@55

LOL

@56

It's true. Whenever I get a referee request from TL I always roll my eyes at the urge to decline, but it's exactly these kinds of papers that make me want to continue reviewing for them.
Problem is, I would have asked for a lot more experiments than the ones reported in the manuscript as well as a few explanations of unclear and muddy points. And then I'd simply see the paper published online "as is" 2 or 3 weeks later.

Permalink to Comment

58. MedChem on September 22, 2010 9:52 AM writes...

56:

LOL!

57:

In the past few months I have rejected a bunch of TL manuscripts in a row, all of which are from India. Talk about irrelevant incremental "improvements" that nobody cares. I wonder if the editor is having second thoughts about sending me more manuscripts.

Permalink to Comment

59. milkshake on September 22, 2010 9:59 AM writes...

@ 41, Nick:

607 mg (1.5 mmol) of (S)- CbzNH-NH-CH(Bn)CO2Bn (hydrazino version of phenylalanine benzyl ester with Cbz on second nitrogen) and 1.05g of FmocSer(OBn)Cl (2.41 mmol, freshly prepared from FmocSer(OBn)-OH and oxalyl chloride 1.2 eq. in DCM, 1 drop DMF, RT, overnight) was dissolved in anhydrous DMEU 4.5mL and AgCN 660mg (4.93 mmol) was added. The mixture was stirred at 80 C bath for 90 min and protected from light. Cooled, diluted with ether, the precipitate filtered off and washed with ether. The filtrates were washed with half-saturated sodium bicarb (twice) and water, the aq phase reextracted with ether. Combined extracts dried with Mg sulfate, evaporated, residue purified on silica 30g in DCM-EtOAc 30:1 mix. Y=1.187g (98% th) of a white amorphous solid, uniform on NMR, LCMS
DMEU is 1,3-diMe-2-imidazolone, I used anhydrous stuff from Fluka. (The original jap procedure called for HMPA as a react solvent). One can also do this acylation in benzene but it is noticeably messier.

Permalink to Comment

60. alig on September 22, 2010 10:27 AM writes...

Actually if the chemistry was using samarium to couple an acid and an amine, it would have been interesting. But they were using samarium as a general base, not a coupling reagent. There is nothing wrong with the currently available general bases used in the coupling of acid chlorides to amines. If you can form a stable acid chloride, it is usually the best method for forming amides, but often you cannot make an acid chloride. When you can't make an aicd chloride, you have to use the expensive, non-atom economical reagents (HATU, Pybop etc) where alternatives which are cheaper and work as well would be great.

Permalink to Comment

61. Nick K on September 22, 2010 2:23 PM writes...

Thanks, Milkshake! (tips hat)

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62. European Chemist on September 22, 2010 2:40 PM writes...

58

I, on the other hand, actually think that the Editor sends me TL manuscripts whenever we wants a swift rejection. And I kind of start feeling bad after the 'n'th rejection.

Permalink to Comment

63. Petros on September 23, 2010 2:25 AM writes...

Hmm

The preprint says "This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain."

Will the editors check this7

and the authors state
"Our interests in utilizing samarium metal
in organic synthesis have led us to investigate samariumpromoted reactions for the synthesis of amides.[16]"

All three papers cited use Sm in the formation of Bayliss Hillman adducts, not in amide formation!

Permalink to Comment

64. sepisp on September 23, 2010 9:06 AM writes...

Well, if you can be bothered to look up Wikipedia on samarium, you'll see that it forms a dichloride and a trichloride. That is to say, it would be stoichiometric at 1/3 eq. if 100% of the chlorides produced would be SmCl3. Given the mechanics of the reaction, it would be insane to claim a catalytic reaction.

Then again, I think there's some minor discovery value in stating the fact that you need a base that's nonnucleophilic and doesn't interfere with you reaction. What about other rare earths - REEs are not that rare, in fact, and need not to be ridiculously expensive. Don't also forget that tetraethyl lead was produced using metallic sodium for chloride removal, the process being hardly clean, and TEL was not a pharmaceutical. Furthermore, in-situ electrochemical reduction was done for tetramethyl lead. It isn't hard to imagine samarium in its place.

Permalink to Comment

65. mad on September 23, 2010 9:47 AM writes...

Funny thought…1000 years from now a space crew is stranded on a sarium rich planet and the only way off is somehow linked to them initiating amide formation. Then the science officer suddenly shouts “Captain I found the answer! Back in 2010 it was discovered that….”

Permalink to Comment

66. John on September 27, 2010 7:10 AM writes...

Is the metal easy to recover after the reaction?
If it is $5000 a kg may not be as bad as it sounds.

Permalink to Comment

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