Sciencemadness Discussion Board

(Organic) Chemistry and Web 2.0

py3rhcl3 - 22-7-2009 at 10:22

I think most of the regulars here do read the totallysynthetic blog so they may be aware of it already.
Today a rather controversial paper was published in JACS as an ASAP where NaH was used to oxidize secondary alcohols to ketones (the asap). Within hours, several puzzled readers of the before mentioned blog are reporting the results of the experiments where they try to reproduce the results of this paper.
I love this idea that the community is critical and is working together and reporting the progress of the research. Just wanted to let you know of this. What do you think?

Nicodem - 22-7-2009 at 12:15

Unfortunately, I will not be able to access the paper till tomorrow, because I'm only have access to it at my job. It is a very suspicious paper judging by abstract already (a strange very pompous discourse unusual for ACS publications), but the oxidation of alkoxides to carbonyl compounds from molecular oxygen is known. However, according to the Totalysynthetic blog, the reaction occurs under inert atmosphere as well, which implies a beta-hydride elimination from the alkoxide. I never heard of beta-hydride eliminations mediated by alkali metals and can't see any viable mechanism for such a reaction, of which the product would be a carbonyl compound and NaH. And this is the major problem here - which was not addressed at TotSyn - that in the case of substrates which are secondary alcohols, such as 1-phenylethanol, the resulting acetophenone would likely get deprotonated by NaH as well as slowly succumb to aldol condensations.

On the other hand, JACS is the strictest journal in regard to the referee system I know of. If the editor allowed the publication (even though still hanging in the ASAP system) of such a paper that at the first glance look like complete BS, he must have gotten some very reassuring replies by the referees. Their correspondence must be a very interesting read!

JohnWW - 22-7-2009 at 13:24

There must be a very serious mistake there! There is NO WAY that NaH could possibly be an oxidant, let alone of secondary alcohols C-CH(OH)-C to ketones C-C(=O)-C, which in fact involves the removal of two H atoms! How on earth could that charlatanism have gotten into the JACS, other than by croneyism or bribery?

On the contrary, NaH, a strong reducing agent, reacts with ketones, the alleged product above, to form ionic enolates C-C(O-)=C plus H2. These figure in varous condensation reactions, e.g. to produce keto-substituted carboxylic acids.

[Edited on 22-7-09 by JohnWW]

DJF90 - 22-7-2009 at 14:23

JohnWW: The oxidation of primary alcohols also involves "removal" of two H atoms.

Nicodem - 22-7-2009 at 14:25

But, it is not claimed that NaH is an oxidant!
Supposedly NaH promotes the oxidation. Obviously the first step is the formation of the sodium alkoxide and H2, but I have no idea how this decomposes to the carbonyl compound. In every redox reaction something gets oxidized (in this case the alkoxide) and something gets reduced by the equal amount of electrons. So what is the product of the reduction part of the redox equation? If I understood that blog correctly, the authors of the paper claim that NaH regenerates during the oxidation of the alkoxide. Now, the only possible mechanism for such a thing is a beta-hydride elimination, one of the most common reactions in organometalics, that however commonly occurs only with transition metals (but under heating also with other metals like Al, for example). A highly unlikely mechanism in my opinion, even though I just realized that beta-hydride elimination is actually known in the alkali metal series (for example, n-BuLi when heated decomposes to LiH and butene).
Until someone posts the paper, there is no way to say if they provided enough evidence for anything of this kind.

Bolt - 22-7-2009 at 19:25

Reductive and Transition-Metal-Free: Oxidation of Secondary Alcohols by Sodium Hydride
Xinbo Wang, Bo Zhang and David Zhigang Wang
J. Am. Chem. Soc., Article ASAP, Publication Date (Web): July 21, 2009 DOI: 10.1021/ja904224y

The potential utilities of the simplest hydride reductant sodium hydride (NaH) as an oxidation promoter have long been overlooked. Uncovered here are some unprecedented reactivities of this classical reagent under very mild conditions, including alcohol oxidation, tandem allylic alcohol oxidation−hydride conjugate reduction, and aldehyde oxidative amidation. These readily implementable transition-metal-free processes feature exceptional material accessibility, operational simplicity, and environmental compatibility.

Attachment: Reductive and Transition-Metal-Free Oxidation of Secondary Alcohols by Sodium Hydride.pdf (225kB)
This file has been downloaded 2950 times

turd - 23-7-2009 at 04:57

Quote: Originally posted by Nicodem  
So what is the product of the reduction part of the redox equation?

Just stating the obvious: The mechanism you and the Chinese propose has as total chemical equation of
alcohol + NaH --> oxo-compound + H2 + NaH

Therefore - formally - NaH is the catalyst of a disproportionation reaction.

Of course if it was as simple as
Na-alkoxide --> NaH + oxo-compound

then one has to wonder why use nasty NaH, when you could simply use Na. There must be other reasons for this result.

[Edited on 23-7-2009 by turd]

Nicodem - 23-7-2009 at 08:24

I went to read the paper and there were many, too many upseting issues, so I decided to just review the thing and post here my comments.

“We herein report on an exceedingly simple secondary alcohol oxidation protocol that employs the widely available sodium hydride (NaH) as the oxidant.”

Sometimes they claim NaH is not an oxidant, but just a reagent that promotes oxidation, and in sentences like this the make a slip an claim it as an oxidant (which is nonsense since NaH chemically can not accept any more electrons than it already has).

“That is, the strong reducing agent NaH here unusually promoted alcohol oxidation chemistry with remarkable efficiency.”
“NaH is widely known for its strong basicity and reducing power…”

NaH on its own can not be considered a reducing agent for organic synthesis, because the only thing it can reduce is protons from acidic substrates into H2. It can not reduce functional groups of the substrate and it de facto only works as a very strong base.

“The formation of isomeric imidazole-derived a,b-unsaturated ketone 19 (E/Z ) 3:1) from its (E)-allylic alcohol precursor was particularly interesting as it implied a reversible hydride conjugate reduction event following the alcohol oxidation.”

This makes no sense to me. They obtained the product of normal allyl alcohol oxidation (according to the structure of 19 as well as according to the text) and yet the talk about “hydride conjugate reduction event following the alcohol oxidation” which would yield the saturated product. Maybe someone else can explain what they mean with this?

Scheme 4 shows a 1-heteroarylalil alcohols to heteroaryl alkyl ketones transformation and claims it as “NaH-Promoted Tandem Alcohol Oxidation-Hydride Conjugative Reduction of Heterocyclic Allylic Alcohols”. This, in my opinion, is a wrong claim since the process looks like just the common base catalysed isomerization of the double bond promoted by the CH acidity of the Het-CH(OH) group. The isomerization, which surely occurs on the alkoxide, results in the enolate anion which after quenching gives the resulting ketone. Their claim is simply against the Occam’s razor rule of science, because they provide no evidence for a new mechanism instead of the already known old one. Their hypothesis that the reaction occurs via oxidation of Het-CH(OH)-CH=CHR to Het-CO-CH=CHR followed by the 1,4-addition of a hydride is flawed since NaH can not reduce anything but protons. The heterocycles used are all such that enhance the acidity of the side chain’s CH group which is consistent with the classical isomerization mechanism.

“The thiazole ketone 25 was furnished in 86% yield in just 2 h, showing an impressive level of efficiency.”

No wonder! The thiazole heteroaryl group is one that strongly increases the CH acidity of an alkyl side chain on position 2. Another indication that what they observed is just a normal base catalysed double bond isomerization.

From the supporting info: “All reactions were carried out in glassware under a nitrogen atmosphere with dry solvents.”

This is actually the only unexplainable claim. If the reactions would be carried under aerobic conditions, then it wouldn’t be anything special. That alkali alkoxides in solution slowly react with oxygen to give carbonyl compounds is generally known. But under anaerobic conditions the beta-hydride elimination is the only viable mechanism of those known. The guys at TotallySynthetic found out that under anaerobic conditions the reaction gives little conversion, unlike what the authors of the paper describe. Instead under aerobic conditions the conversion approaches the one described in the paper. So, either the authors mistakenly took the O2 cylinder for nitrogen inert atmosphere use, or they are bullshiting us. Also it appears that 2eq of NaH are truly needed if the reaction mechanism is the good old alkoxide decomposition via oxidation with O2. Namely, the other equivalent of NaH is needed to deprotonate the ketone products that have alpha-hydrogens so that they immediately form the enolates instead of undergoing base catalysed aldol self condensations.

There are many other things in the paper that were upsetting to some degree, but there are also many interesting findings reported. However, most things are not presented properly. The paper is very problematic regarding the experiments conditions and them being evidence to their hypotheses. The back loop where their hypotheses should be verified by more ingenuous experimental work is also not proper. For example, they hypothesize either a beta-hydride elimination or a hexahedral transition state as reaction mechanism, both would regenerate NaH, but they never demonstrate how much NaH is left after the reaction (a simple volumetric test would give them a rough measurement). If the mechanism involves molecular oxygen, then NaH is not regenerated but one equivalent lost in the reaction with the acidic OH group and the other with the ketone product (if this contains alpha-hydrogens). This also explains why NaOMe or Na were not effective in the reaction, while NaHMDS worked in some cases. Both, NaOMe and Na cause the ketone product to succumb in side reactions (either aldol or pinacol, respectively), while NaHMDS protects the product via quantitative deprotonation to the enolate.

turd - 23-7-2009 at 10:10

LOL. Now that you say it - Scheme 4 is one of the bigger WTFs i've seen lately. This is nothing more than our beloved base catalyzed allyl -> propenylbenzene isomerization and they caption it "NaH-Promoted Tandem Alcohol Oxidation-Hydride Conjugative Reduction of Heterocyclic Allylic Alcohols" :o

Seems like the referee system of JACS is not that good after all. But to me this does not come as a surprise. In a journal that publishes nearly 20000 pages a year, not every article (or communication) can be good. In organic chemistry it's probably not that bad, but for thoroughly reviewing an article in my field you need at least one week (where you do not much else). Now consider that people do not only want to review, but also work and publish and do the math: you'll see that given the sheer volume of stuff that is published the system cannot work. And we witness it every day.

py3rhcl3 - 23-7-2009 at 11:16

I do not want to interrupt the ongoing discussion, but I just wanted you to know that the first results of the "blog review" are in and it appears that oxygen is the actual oxidizing agent (who would have thought that :o). For deeper insight read here and here (further down in the comments).

kmno4 - 23-7-2009 at 21:41

Quote: Originally posted by py3rhcl3  
who would have thought that :o

Every good chemist should have thought about this possibility :P

Besides, I do not know why this journal is still called JACS. There are so many Chinese articles in it (and in other journals from ACS too) that this name should be changed.
Maybe " Mainly Chinese Journal of Chemistry" (MCJC) ?

[Edited on 25-7-2009 by kmno4]

bfesser - 27-7-2009 at 09:48

The_Davster - 13-1-2010 at 11:23

Click on the pdf button.
"paper withdrawn for scientific reasons":P

Fleaker - 13-1-2010 at 14:55


It started with an eyebrow-raising, topsy-turvy claim that a strong reducing agent could efficiently promote oxidation, and ended up demonstrating that blogging can be an influential force for science that is able to act as an informal yet powerful peer review system.

Even the RSC is doing it! It's not a reducing agent, it's a BASE!

[Edited on 13-1-2010 by Fleaker]

ziqquratu - 14-1-2010 at 13:13

It's not exclusively a base - it CAN act as a reducing agent, although (obviously) it isn't commonly used for that purpose.

A quickly Googled example (in which case it wasn't even DELIBERATELY used as a reducing agent!):

Fleaker - 15-1-2010 at 18:07

This is true. Perhaps I was worked up in reading that garbage paper where it talks about its well-known reducing properties and then goes on to say it is an oxidizer.

Correct me again if I'm wrong, but NaH is hardly a common reducing agent.

Thank you for the example.

[Edited on 16-1-2010 by Fleaker]