Dropping the Hammer…

Hai-Tao Zhu, Ke-Gong Ji, Fang Yang, Li-Jing Wang, Shu-Chun Zhao, Shaukat Ali, Xue-Yuan Liu, and Yong-Min Liang Electrophilic Carbocyclization of Aryl
Propargylic Alcohols: A Facile Synthesis of Diiodinated Carbocycles and Heterocycles
Organic Letters January 20, 2011

Some people believe that, if it appears in an ACS Journal then its cutting edge research, that the work that was done is phenomenally important or impactful. I mean it must be right? The ACS promotes themselves as the most cited and most trusted. And frankly, if I have to pick between an ACS procedure and a Tetrahedron Letters (no slight against that journal, because they got me my first publication!), I’d choose the ACS one because in my experience they are more likely to work. Notice that I said more likely. There are some articles that are, what I believe to be, crap or fudged data. And it’s been appearing more and more lately, especially with yield fluffing and what I’m convinced are either forged spectra or simply known samples doped with slight impurities to make them seem real. If you think I’m crazy, go talk to Professor Sames. He had a scandal with a student who did the doping thing. Science in a lot of ways has become too competitive…but why am I talking about this instead of reviewing?

style=”text-align:center;”>Propargyl Alcohol Dissociation Yielding Allenes

Well, this is one of those articles that won’t get a favorable review. You may disagree with my interpretation as they may be wrong as well, but I just was very skeptical of this article from the beginning. I mean the concept seems interesting but there are just too many holes and too much overlap with previous work. The article begins by surveying the literature regarding the synthesis of various cyclic systems by electrophilic carbocyclization. They then state that allenes are rarely used in such cyclizations as they are often difficult to work with. So they decided to explore what can be done with them. Now here’s where I got sketched out. I checked into their references of themselves just because I wanted to see what they had done previously with this chemistry. Notice anything similar between this JOC article and the CEJ communication? I mean yes granted one is an article and one is a communication. But still, the fact that they are so closely published and date and on THE EXACT same material leads me to believe they double submitted, which to me is highly unethical. But anyway moving on, in this article, as in their others they focus on propargyl alcohols. Not surprisingly, these alcohols tend to form carbocations under acidic conditions. The authors then state they form positively charged allenes via resonance with the triple bond which is perfectly acceptable to me. Now here’s where I ran into my big problem: the mechanism. They propose this as their mechanism for how iodination occurs (and consider this a general mechanism where the phenyl group can be replaced by a hydroxyl group or amine for their other work):

Their “mechanism”, like much in this article leaves much to be desired (and no, they didn’t put in the question marks in this article but they did in the CEJ article :P). I did do some digging myself and found that you can’t simply cyclize (as far as I could find) a system such as the one above with just acid. You just get the alpha-beta unsaturated ketone instead. So the iodine must be doing something, but what? And how do you get the cation in the first place? Well to answer the latter, in the article they stress that the solvent (nitromethane) must be wet. That’s only a little ambiguous and they didn’t give an explanation of why there was this requirement (even in their other papers). And they were surprised that certain solvents like ethereal solvents (dioxane, ether) and acetonitrile didn’t work well if at all. I’m not at all. You are probably getting a Ritter-like reaction with both of those types of solvents. Or you are decomposing the solvent. How? I think, to answer both the “wet” issue and the solvent parameters, all that is happening is the generation of small amounts of HI in situ. There is two possible ways this could occur. I know if you breathe the vapors you can generate HI in your lung from being in a wet oxygenated environment causing irritation. So it’s not inconceivable that the same sort of thing is happening here and would explain the “wetness requirement”.
Another possibilty is that the alcohol reacts with molecular iodine and gets oxidized to a ketone. An water containing solvent could assist in promoting this oxidation and possibly serve a limited role as a base (instead of using the propargyl alcohol like I suggested). If this was a mere side reaction that’d be fine and, since they never got 100% yields, this is certainly a possiblity. That would allow for the generation of I- and H+. Moreover for each round of reaction my oxidation mechanism generates 3 equivalents of the desired product to the undesired ketone and considering their yields capped off around 75% this makes some sense (which leads me to an aside, in their abstract image they had an R3 coming off the aryl ring they never had a substrate where R3 was anything other than H, just another reason why this article was low quality). At least this gives an idea as to how it works rather than just saying iodine *magic* iodinated product. I mean I can see, once you get the iodinated allene, how iodine could catalyze electrophilic addition by the arene. But also question some of their NMRs. They are seriously poor resolution and you’d never know if you had a di-iodinated or possibly a mono-iodinated product. They also aren’t very clean either. I even question the chemistry. If their mechanism is correct, the cyclization is essentially (when forming the five membered rings) a 5-endo-trig reaction. I don’t know if aryls will follow Baldwin’s rules but if it does, this reaction ain’t favorable. Moreover they fail to mention one very very important thing. All the groups attached to the hydroxyl carbon were carefully selected to be very cation stabilizing (aka aryl or tertiary). Not surprisingly, the tertiary needed heating in order to go. So essentially if you didn’t want groups off the hydroxyl or wanted one alkyl group, you are boned. It really kills the scope of this method.

They did do something interesting next. They attempted and succeed in forming 7-membered di-iodinated compounds by starting with aryl alkynyl ethers. Not too shabby, I think this was one of the better more believable parts of the article. Again the method has the same limitations as before but does give much more useful and hard to get at products (particularly for those interested in natural product synthesis). They even apply their method in a limited synthetic manner by doing oxidizing one of their six membered di-iodinated products to its corresponding napthyl derivative and then doing a Sonogashira in a coupling reaction to two p-methoxyphenyl acetylenes. They suggest that this particular product could be of interested as a fluorescent material. While it ended on a better not, I really do not think this chemistry was novel enough nor written at the standards of an ACS journal especially Organic Letters. If this had been in let’s say Tetrahedron Letters or Organic and Bimolecular Chemistry (and those are excellent journals, don’t think I am slighting them) this would of been acceptable. Its known chemistry being done on a slightly different substrate. But Organic Letters? I think they let this one slip through.


  1. good text

  2. […] a I+ source. attempting iodocyclization (which has been pretty popular lately and I even reviewed an article a while back). While the desired reaction did occur, yields were unacceptably low even […]

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