It’s a TPAP!

Schmidt, A.-K. C.; Stark, C. B. TPAP-Catalyzed Direct Oxidation of Primary Alcohols to Carboxylic Acids through Stabilized Aldehyde Hydrates Org. Lett. ASAP July 27th, 2011.

What stops chemistry dead in its tracks? Waiting for chemicals and supplies. While we had another relatively productive week in the Leadbeater lab, our progress has been slowed (on basically all fronts) by either chemicals or equipment not coming arriving on time. In fact, one of our chemicals has been delayed for over a week now. Despite these setbacks, my lab-mates and I have found plenty to do. Friday, I had the “exciting” opportunity to work with t-Butyl Lithium again. For those unfamiliar with this compound, it’s somewhat pyrophoric, and by that I mean it makes a beautiful purple flame as soon as it hits air. While I’ve worked with it before several times, it’s always a little bit of a rush each time. After titrating it (WHICH IS A MUST!!!! Cannot stress that enough, our bottle said it was 1.7 M but after performing the titration procedure outlined by House we found it to be 2.4M!), I performed a Lithium-Halogen Exchange (LHE), which is one of the coolest reactions I know of. And it worked perfectly and was over in all of 10 minutes even at -78 oC! It’s amazing how fast those reactions are.
Our undergrads are finishing up this week and will be presenting their work shortly. My lab-mates and I are working closely with them to make sure both their presentations and posters come out well. Some of them that go to UConn will be staying on with us and I’m excited to have them in the lab. So unfortunately that’s about it for my week, nothing terribly exciting to report. However, I did find a very well-written article outlining a pretty cool oxidation in the lit this week so let’s get to it!
So if you know anything oxidation chemistry, you know that there are a vast number of reagents out there. You have the traditional Jones oxidation, TEMPO or Oxoammonium Salt based Oxidations, Pinnick Oxidations, MnO2-based Oxidations, Hypervalent Iodine (e.g. Dess-Martin Periodinate), and DMSO-Based (e.g. Swern or Moffat. A great (general) summary of these and some other oxidations can be found here and here. One of, in my opinion, the lesser known oxidations is the Ley Oxidation (using the Ley-Griffith Reagent, TPAP). Typically, the reaction is run anhydrous to give aldehydes from primary alcohols (and considering RuO4 is a tad bit expensive, the reaction is usually catalytic in RuO4 with a bit of NMO tossed in to regenerate it). However, in the absence of a drying agent or with the addition of water, carboxylic acids can be obtained instead. It works something like this (or at least how I understand it anyway…):

However, Ley oxidations in which carboxylic acids are the major product are lesser known in the literature. In fact, until this paper there had never really been an optimization for the acid. The majority of focus had been on stopping at the aldehyde stage. Just adding water to the reaction doesn’t always do the trick because some aldehydes form hydrates at very low levels (i.e. 0.001%). While eventually the reaction would proceed, it is far from effective in a normal time frame. However, this article isn’t primarily an oxidation paper. Its somewhat of a molecular interactions paper. The main focus is in fact using N-methylmorpholine N-Oxide to stabilize hydrates of aldehydes. Initially, the authors took a somewhat electron-deficient aldehyde (which hydrate better than electron-rich ones) and compared the ratios of the hydrate to the aldehyde via H-NMR. They found that by dumping in 10 equivalents of NMO in wet MeCN or DMF, they could alter the ratio from 99:1 aldehyde/hydrate to 67:33. Both observations make sense. Hydrate formations is entropically unfavorable and, according to the article, enthalpically as well. However, by placing NMO into the mix, the hydrate can be stabilized by a hydrogen bonding model:

With this valuable information in hand, they applied it to the Ley oxidation. They still had a bit of work to do here though. First, they needed to establish the optimal water to NMO ratio. Too much water and the catalytic cycle could be destroyed. They found the best ratio to be 10 equivalents of a 1:1 mixture of NMO:H2O. Solvents such as acetone, DMF, DCM, and MeCN were screen and so long as the NMO and TPAP were soluble, the reaction proceeded well (with MeCN proving to be the best). Once these variables were examined, they jumped straight into substrate screening. They looked at everything from branched alcohols to benzyl alcohols to those with halide or epoxide functionalities. In the case of the aryls, a strong dependency on the electronics of the aromatic ring was noted. More electron-rich arenes seemed to fair far worse than their electron-deficient counterparts (likely ability of the intermediate aldehydes to hydrate readily). They seemed to have a pretty good mix of alcohols and yields were relatively good on most substrates.
Overall, while not a groundbreaking article, I really enjoyed this one. I felt it was well-written and shows how intermolecular forces can be exploited. Hats off to the Stark group for a job well-done. That’s all for now, Ckellz…Signing off…



  1. Nice article – love the title! A quick question: the mechanism you’ve drawn has RuO4, but does that species actually exist in a Ley oxidation? I’ve never done one, but I thought they were considered pretty mild, due to only using RuO4- (perruthenate). RuO4 (ruthenium tetroxide; I have used this) is a crazy oxidant which does all kinds of wild stuff like oxidise benzylic positions and double bonds, convert cyclic ethers to lactones and destroy electron rich aromatic rings. Can NMO convert the RuO4- you put in to RuO4?

    Oh, and one small type-o – Dess and Martin’s reagent is a periodinane, not a periodinate.

    • Thanks!!! You are indeed right that it is the perruthenate anion. I didn’t depict it as such but I did some research after you commented and yes in fact it should be the anion that is in play. A more detailed mechanism would show that the anionic form gets attacked and a hydroxyl group is lost (at least according to the articles proposed mechanism). That leaves you with a Ru (V) species that is also anionic (the RuO3 I showed also should be negatively charged!). Ruthenium tetroxide is never invoked and yeah, it is a ridiculous oxidant. I’m fairly confident NMO cannot form this species in situ. And thanks for the periodinane thing. I don’t know why I keep saying periodinate, maybe because I’m used to NaIO4 as sodium periodinate. It actually came up in my lab this week when we were discussing oxidations (DMP being one of them). I was proven wrong there too :P. However, if you’re looking for an awesome lesser known oxidant, oxoammonium salts are the way to go. They are so easy to do and have worked every time for me. I might do a test this week to compare an oxoammonium oxidation vs. a TPAP oxidation see which is easier because this paper gave a seemingly straight forward prep of TPAP and we have plenty of our oxoammonium salt on hand.

  2. […] step is hydration of the intermediate aldehyde. This is in line with previous work (and a previous post by myself) using TPAP. They further support this finding by conducting a relative rate study, […]

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