Talk:Proline-catalyzed aldol reactions

andOrganocatalysis User:Zghajos From Wikipedia, the free encyclopedia Jump to: navigation, search Remarks to the Wikipedia Organocatalytic aldol reactions

Zoltan G. Hajos zghajos(AT)t-online.hu

The reaction scheme (a) as shown in the Wikipedia Organocatalytic aldol reactions page has only been described in the Hajos, Parrish Patent (b) and the Hajos, Parrish paper (c).

Since Hajos and Parrish worked at ambient temperature using a catalytic amount (3% molar equiv.) of (S)-(-)-proline they could isolate the optically active intermediate bicyclic ketols a prerequisite of elucidating the reaction mechanism. This was most likely the reason for Professor Claude Agami to call the reaction the Hajos-Parrish reaction in his paper in J.Chem.Soc., Chemical Commun., 1985, 441-442 (d).

The Hajos, Parrish Patent (b) also described the Asymmetric synthesis utilizing (S)-(-)-proline even in the absence of added solvent.

The last few lines of the Hajos, Parrish 1974 paper read: "We believe our results may be considered an example of a simplified model of a biological system in which (S)-(-)-proline plays the role of an enzyme." This has been referred in a publication by Mohammad Movassaghi and Eric N. Jacobsen of the Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA: The Simplest "Enzyme" Science, 6 December 2002, Vol. 298, 1904-1905 (e).

The above is also described in the Benjamin List Tetrahedron report number 613 in 2002 (f). This Tetrahedron report shows that the Schering group executed the reaction under non biological conditions using (S)-Proline (47 mol%), 1N perchloric acid, in acetonitrile at 80 degrees C. Hence, they could not isolate the Hajos, Parrish intermediate bicyclic ketols. The original 1985 naming of the reaction by Claude Agami (d) has been expanded in this 2002 paper (f) by adding three more names of the Schering group.

References to the Zoltan G. Hajos Remarks. a.http://upload.wikimedia.org/wikipedia/commons/d/de/Organocatalytic1.gif]

b. Hajos, Z, G.; Parrish, D. R. Asymmetric Synthesis of Optically Active Polycyclic Organic Compunds. German Patent DE 2102623, July 29, 1971.

c. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974,39,1615.

d. Agami, C.; Levisalles, J.; Puchot, C. J. Chem. Soc., Chem. Commun. 1985, 8, 441-442. doi:10.1039/C39850000441

e. Movassaghi, M.; Jacobsen, E. N., Science, 2002, 298, 1904-1905. doi:10.1126/science.1076547

f. List, B, Tetrahedron 2002, 58, 5573-5590 doi:10.1016/S0040-4020(02)00516-1 references 12 doi:10.1021/jo00925a003 and 13 doi:10.1002/anie.197104961

• Thanks Zoltan for your comments, I have incorporated some of it in the article itself but feel free to make edits yourself. I have been trying to find the German patent (nowadays I would expecting these patents to be freely available on the internet) but no luck. Help would be appreciated V8rik (talk) 17:45, 17 January 2008 (UTC)

German patents are not as freely accessible as US Patents.You have to establish an account with Delphion(http://www.delphion.com).Of course, you do have access to their paper in Angew.Chem.Intl.Ed.Engl.10(1971);pp. 496-497.zoltan —Preceding unsigned comment added by Zghajos (talk • contribs) 12:33, 18 January 2008 (UTC) To V8rik: here is a link which could be helpful http://commons.wikimedia.org/wiki/File:Hajos-Parrish-German-Patent-1971.pdf Zghajostalk

• Thanks for your reply, by the way: you can sign your comments by adding four tildes ~ in a row V8rik (talk) 17:39, 18 January 2008 (UTC)

• If there's a difference in the Hajos-Parrish and the Hajos-Parrish-Eder-Sauer-Wiechert reaction, then why don't we create a separate article for the first one? And if there's no difference, then why do we add the name of those three gentlemen to the name of the inventors? What is their added value? Tom A. Jansen (talk) 18:45, 28 January 2008 (UTC)

Concerning the lack of understanding of the reaction mechanism. The person who wrote that segment is obviously unaware of the fact that Hajos and Parrish needed the starting material triketone for their asymmetric synthesis. The synthesis of the starting material has been described in a Research Article entitled "Synthesis and conversion of 2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedione to the isomeric racemic ketols of the [3.2.1]bicyclooctane and of the perhydroindane series" by Zoltan G. Hajos, David R. Parrish J. Org. Chem., 1974, 39 (12), pp 1612–1615 DOI: 10.1021/jo00925a002 Publication Date: June 1974.Zghajos (talk) —Preceding unsigned comment added by Zghajos (talk • contribs) 00:18, 27 February 2010 (UTC)

Due to a correction by V8rik the real Zoltan Hajos is compelled to follow through. You allow text which is in fundamental error. How can anyone in his or her right mind believe that the isolation and characterization of intermediates of any reaction hinders the development of science, and shows the lack of understanding of the people who first uncover any reaction on the surface of our Globe? Zghajos talk-- —Preceding undated comment added 22:18, 12 March 2010 (UTC).

Just flipped through the article, and it looks pretty good. I think the role of computations here has been downplayed. This is really a case where they've played an important role in understanding precisely how proline catalyzes the reaction. Also, there's a nice discussion of the various mechanistic data and potential mechanisms for the reaction. However, the article does not seem to come to any conclusion regarding which mechanism is correct, when in fact, pretty much everyone agrees with the List-Houk mechanism (correct me if you disagree). There's also a kind of cryptic statement: "The Hajos and Parrish experiment with a stoechiometric amount of labeled water (H218O) supported the carbinolamine mechanism." It's now been shown that 18O is, in fact, incorporated in the product when the reaction is done very carefully (PNAS 2004 101 5839). Additionally, Gschwind has recently detected enamine intermediates by NMR (ACIE 2010 49 4997). So with respect to Dr. Hajos, I think the carbinolamine mechanism is, at this point, considered relatively unlikely. In summary, this is a nice article, but it's somewhat disorganized. A summary of the accepted List-Houk model would be welcome.

Personally, I think the Seebach-Eschenmoser proposal is very controversial at the moment, and I might even go so far as to say that the prevailing view in our department seems to be that it's unlikely. While there is no question oxazolidinones are detected in the reaction mixture, there seems to be little evidence that says that the oxazolidinones are actually on the reaction coordinate. There's a recent study by Sunoj that indicates that the pathway should be much higher energy (ACIE 2010 49 6373) and furthermore, that the incorrect diastereoselectivity is predicted if the reaction goes through enamine carboxylate. This makes sense, if you consider that the mechanism can no longer stabilize the forming alkoxide with a hydrogen bond. These reactions are run in DMSO or DMF, neither of which are good hydrogen bond donors.

Also, I detect something of a prejudice against the Schering group. Certainly, they did the reaction under harsher conditions. But it seems unnecessary to point out whether one set of conditions were more "biological" than the other. Finally, the introduction is convoluted (very parenthetical) and hard to understand. So there's some great material here, but it needs some attention. Eugene Kwan (talk) 07:03, 23 November 2010 (UTC)

Neutrality

With respect to Dr. Hajos, I don't believe it's appropriate for someone to write about their own research here. The discussion of mechanism in this article seems biased towards the originally proposed mechanism. Statements like "It is interesting and surprising that Eder, Sauer and Wiechert have not attempted to explain the reaction mechanism" are unprofessional and unnecessary. I think virtually everyone agrees that the List-Houk mechanism is the right one these days, but the article is now so convoluted it's impossible for a person unfamiliar with this work to tell. Also, why is there discussion of other aldol reactions? For example, the discussion of the nitroso aldol reaction seems out of place. I think we need to do some pruning here, and this should be done by someone who's not involved with the chemistry in any way. But I'll wait to see what others think before taking any action. Eugene Kwan (talk) 15:32, 9 April 2011 (UTC)

• Agreed, we should welcome contributions from specialists in the field but not if they are biased. V8rik (talk) 21:25, 9 April 2011 (UTC)

Is it true that the perchloric acid / proline assisted transformation gives the same bicyclc ketols as the Hajos - Parrish procedure? That is what the text of Lecture 34 implies: "Eder and co-workers used harsher conditions involving perchloric acid at elevated temperatures, but accomplished the same transformation." See: http://isites.harvard.edu/fs/docs/icb.topic776365.files/lecture%2034.pdf Zghajos (talk) Zghajos (talk) 14:04, 28 January 2012 (UTC)