Paper #6 – Checking stereochemistry

A great discussion today of paper #6 – Synthesis of Tertiary α-Hydroxy Acids by Silylene Transfer to α-Keto Esters, OL, 2007, 4651. It was fun to have so many participants and so many ideas.

The take-home lessons stressed the importance of:

• asking yourself hard questions about unfamiliar reaction mechanisms (you know which questions to ask)
• acquainting yourself with unfamiliar technical terms (a frequent problem with organometallics because the reagents are not organic)
• not taking stereochemistry on faith

Going a bit farther with the third point …

Paper #3 – Question List

Part of your “background” assignment for paper #3 was to propose two scientific questions for class discussion. I thought it might be interesting to share all of the questions I received. You might also be curious about the questions I constructed before class …

Paper #3 – Driven by discovery or hypothesis?

This is the last time that I will beat the Hypothesis Horse, I promise…

Paper #3 (“Highly Selective Diels−Alder Reactions of Dienophiles with 1,3-Cyclohexadiene Mediated by Yb(OTf)3·2H2O and Ultrahigh Pressures”) looks like a classic example of discovery-driven research: vary a bunch of experimental conditions (T, P, Lewis acid, stoichiometry, dienophile) and collect the results in a table. Lots of data were generated. No competing models or hypotheses were ever discussed. Seems like an open-and-shut case for discovery-driven research. Game over.

But wait a minute. Isn’t there a rather obvious hypothesis lurking in the third sentence!

“On Water” Reactions

We discussed the behavior of Diels-Alder reactions in water (and in aqueous salt solutions) in class in connection with paper #2 – Diganta Sarma and Anil Kumar, “Hydrophobic Effects Are Dominant over Secondary Orbital Interactions for a Simple Diels-Alder Reaction in Salt Solutions,” OL, 2006, 2199. As part of that discussion, I mentioned that “on water” reactions had become all the rage.

You may have thought that the “on water” procedure was nothing more than a chemical curiousity, but a brand new review article of “on water” reactions has just appeared: Arani Chanda and Valery V. Fokin, “Organic Synthesis “On Water”,” CR, 2009, 725. Since this is a review article, it contains many examples and is rather long, but I strongly encourage you to read the following sections anyway: “on water” Diels-Alder chemistry (p. 726), followed by “on water” 1,3-cycloadditions (p. 728) and Claisen rearrangements (p. 731). Although I won’t have much more to say about “on water” chemistry in our class, we will discuss these other reactions as they occur in organic solvents.

Paper #1 – The Aftermath

A few observations about our discussion of paper #1 last Wednesday:

I enjoyed our discussion very much. I thought everyone made good contributions and I hope all of you will continue to participate at this level.

Sadly, we didn’t get a chance to discuss the main findings of the paper so at the end of class, I encouraged you to review the contents of Tables 1 and 2, and also to make sure that you understand what the authors observed regarding regio- and stereoselectivity. Notice that the authors also refer to endo selectivity, to diastereomeric excess (de) and to diastereomeric ratios (dr). I expect you to be able to explain all of these terms. I also expect you be able to draw all of the isomers that are involved in these comparisons. If you have any doubts on this score, please come see me! (And bring your drawings with you.)

You might have been disappointed that, despite the paper’s brevity, we discussed less than half of it. I’m afraid that this will be the normal outcome for many of our discussions. The gap between the 201/202-level of understanding and the research-level of understanding is large. In addition, research publications are information-dense. A single paragraph may offer a lot to ponder. Since my main goal in this first discussion was to point out these gaps and try to bridge them, we had our hands full. That said, I’m always willing to continue our discussions outside of class. Come see me.

Jr. Qual note: Juniors should reflect on the classroom discussion of the de?/activating? nature of the cyclopropylidene substituent on dienophile, 6. Notice that this compound created an opportunity for an open-ended analysis of structure-reactivity relationships. This discussion illustrates the kind of analysis that Pat and I expect from you, namely, a rigorous application of ideas from 201/202 (and beyond) to any new problem that arises. You need to be conversant with these “old” ideas and you need to have some reasonable notions about how to apply them. More generally, you can expect us to sieze on some narrow statement found in a paper and expand this into a general discussion of basic principles.

The best way for you to get ready for this is to practice active reading. This means testing the depth of your understanding of what you read. It is possible that you can do this on your own, but discussions with other students offer an easier route. If the other student hasn’t read the paper, try to explain it convincingly (choose something that you are unsure of). Solicit questions and try to construct convincing answers. If you are working with someone who has read the paper, quiz each other. Don’t make this into a test of memory. You don’t need to be able to recite the paper’s contents. Instead, test each other’s ability to explain the paper.

Stupid @!#$&g abbreviations!

We talked about using Wikipedia and Google to figure out the countless abbreviations that appear in organic chemistry articles. Here are two “officially sanctioned” lists (both are PDF files):

1. The Journal of Organic Chemistry’s list of Standard Abbreviations & Acronyms
2. Hans Reich’s list of Organic Chemistry Acronyms (2002 version)

Since you probably won’t refer back to this post :-), I have added these to our site’s Useful Links list.

Note: The Useful Links list already contains a link to the full list of Hans Reich’s links and it is possible to find the link to his acronym list by scrolling down to “Nomenclature”, but I like shortcuts, don’t you?

Paper 7 – comment on NMR data

One of you wrote “this sucks” next to your NMR assignments. I have to agree. A complete explanation of the 1H and 13C spectra is beyond me.

On other hand, while I wish I had chosen a more accessible set of data, these spectra are typical. Mother Nature is rarely kind. We just have to deal with that.

Here is my quick take on the NMR data along with some subtle relationships that should not be overlooked …

Paper 7 – comment on diastereoselectivity

Today’s paper contains a number of interesting issues. Rather than take several days to create one big long post, I am going to slice my ideas into small chunks and invite your comments.

Here’s one issue: diastereoselectivity in the reactions of 8 with dienes (Table I). Since this reaction involves three distinct steps, there are multiple points at which to stop and ponder selectivity.

• Conversion of 8 (diazo ester) into a metal carbenoid
• Cycloaddition of carbenoid and diene making a divinylcyclopropane
• Tautomerization of divinylcyclopropane to benzofuran

Rationalizing spectral data

NMR – General

As we discussed in class, always use the very best data tables you can find to predict chemical shifts and coupling constant, but remember that spectral data + assignments for a structurally analogous compound are even better than data tables. Some places you can look for spectral data on specific compounds:

• The same paper. Chemists tend to make a series of analogous molecules, replacing a methyl with a phenyl here, or a proton with a methoxy group there. If one of these molecules possesses an easily interpreted spectrum, you might be able to apply this same interpretation to your molecule’s spectra.
• Books. The Reed library contains several compilations of NMR (1H and 13C) and IR spectra (and more). Two favorites of mine are the various Aldrich Libraries (also available online) and “Tables of Spectra Data for Structure Determination of Organic Compounds,” by Pretsch et al. (QC462.85 .T313 1983).
• Online Tables. The Sigma-Aldrich site lets you look at high quality spectra for many of the compounds they sell. You get the spectra, but no interpretation. Another excellent site that actually provides assignments is maintained by Prof. Hans Reich, U. Wisconsin-Madison. I have listed links to four of his data tables, but his site contains much, much more:
  • ¹H chemical shifts
  • HH coupling constants
  • ¹³C chemical shifts
  • CH coupling constants

I have also added some other useful links for organic chemists to the site’s side bar. Check them out before the Qual.

Paper #4 – Importing published models into Spartan

Authors often file additional material with their papers that does not get published in the journal proper. This material is referred to as supporting (or supplementary) information and often contains important additions to the basic paper.

For example, the experiment-based papers that appear in a rapid-publication journal like Organic Letters usually contain only summaries of the research. Detailed experimental procedures, spectroscopic data, and crystallographic data, are published on-line as supplements.

Nearly all journals expect computational chemists to provide supporting information for their papers. At the very least, the chemist is expected to provide lists of the atomic Cartesian coordinates for each model, but other model properties may be demanded too.

A coordinate list can serve two purpose. First, it makes it possible for another scientist to repeat the calculation and check it for errors. Also, and from our point of view more important, a coordinate list can be converted into a “3-D” model so we don’t have to rely solely on the small flat figures in the journal to see what is going on.

You can use Spartan to view published models if you know how to convert the data in the supporting info into a file format that Spartan recognizes. The conversion procedure that I followed for paper #4 can be briefly summarized as:

1. Download & open supporting information
2. Copy atom coordinates to clipboard
3. Paste atom coordinates into a text file
4. Save text file with .xyz extension
5. Open file in Spartan