Sciencemadness Discussion Board - Help needed, failed hydroxylation of alpha ketones.

Hello, I've been a lurker but this is my first post on this forum, I've been stuck on a problem which i feel this community may help with.

So, I've been trying the synthesis of 2-(2-chlorophenyl)-2-hydroxycyclohexanone from 2-chlorophenyl cyclopentyl ketone through direct oxidation of alpha carbon with elemental oxygen and subsequent rearrangement. The method is from the two papers I've linked, but despite my attempts TLC showed little to no conversion of the starting material.

I'm going to describe what i did first, and then the issue:

ATTEMPT 1:
A flask is placed in a warm 30°C water bath, and after being purged with pure dry oxygen an oxygen balloon is connected to maintain the oxidative atmosphere. 2-Chlorophenyl cyclopentyl ketone (2g), triethyl phosphite (2.39g, 1.5 molar eq.) and KOH in anhydrous ethanol (0.54g KOH in 20mL ethanol, 1 molar eq.) are then injected in the flask through a septum one after the other, and everything was stirred at 30°C for 48 hours. Ethanol is then evaporated under vacuum, and the residue washed multiple times with water. An oil was obteined instead of a solid, and TLC revealed that it was mostly starting material.

ATTEMPT 2:
To 2-Chlorophenyl cyclopentyl ketone (2g) and triethyl phosphite (2.39g) in 10mL DMSO a solution of KOH (0.54g) in 10mL DMSO and 5mL ethanol is injected through a septum with oxygen bubbling through the solution. After addition of the base the solution turns from light yellow to deep red, it was left stirring for an hour, after which it was diluted with 200mL cold water. This produced what looked like a beige precipitate, but when vacuum filtration was used everything passed thorugh the filter forming a milky solution. This solution was extracted with a bit of DCM, which was then compared to the starting material on TLC, which showed again little to no conversion.

TLC:

Eluent is 50/50 EtOAc hexane, first dot is ketone starting material, second dot is product and third is a cospot. This is from the first attempt, second is almost identical.

Setup used:

At a glance, the first one you are missing PEG, the second, the cesium.

You shouldn't be making dissociatives, as they shut the brain down.

The first one with peg, to ensure you can duplicate.

arclightshroom - 12-5-2023 at 13:51

Eluent is 50/50 EtOAc hexane, first dot is ketone starting material, second dot is product and third is a cospot. This is from the first attempt, second is almost identical.

Setup used:

At a glance, the first one you are missing PEG, the second, the cesium.

You shouldn't be making dissociatives, as they shut the brain down.

The first one with peg, to ensure you can duplicate.

One of the papers I've linked managed to do it successfully with KOH instead of cesium carbonate, which according to them is better for this substrate

ErgoloidMesylate - 12-5-2023 at 14:17

Eluent is 50/50 EtOAc hexane, first dot is ketone starting material, second dot is product and third is a cospot. This is from the first attempt, second is almost identical.

Setup used:

At a glance, the first one you are missing PEG, the second, the cesium.

You shouldn't be making dissociatives, as they shut the brain down.

The first one with peg, to ensure you can duplicate.

One of the papers I've linked managed to do it successfully with KOH instead of cesium carbonate, which according to them is better for this substrate

If you do that, you have to switch to ethanol.

"The (2-
chlorophenyl) (cyclopentyl) methanone 2 (50.0 g, 0.24 mol), P(OEt)3 (59.8 g,
0.36 mol), ethanol (500 mL), and KOH (13.5g, 0.24mol) were added to a 1.0 L
three-necked flask under an atmosphere of oxygen in a balloon. The mixture
was stirred under 30°C for 48h. When the HPLC showed that 2 was less than
0.5%, the reaction was regarded as completed. In workup procedure, the
mixture was decompressed to remove most ethanol (about 330 mL)

Subsequently, the obtained suspension was diluted slowly with 1500 mL
deionized water, meanwhile, stirred vigorously for 2h at 5-10 °C. The diluted
suspension was filtered to isolate the precipitates which was then washed three
times with deionized water (500 ml) followed by vacuum drying at 50°C to obtain
the faint yellow solid 3 (44.8 g, yield 83.4%, HPLC purity 99.1%)."

[Edited on 12-5-2023 by ErgoloidMesylate]

arclightshroom - 12-5-2023 at 14:25

Eluent is 50/50 EtOAc hexane, first dot is ketone starting material, second dot is product and third is a cospot. This is from the first attempt, second is almost identical.

Setup used:

At a glance, the first one you are missing PEG, the second, the cesium.

You shouldn't be making dissociatives, as they shut the brain down.

The first one with peg, to ensure you can duplicate.

One of the papers I've linked managed to do it successfully with KOH instead of cesium carbonate, which according to them is better for this substrate

Which is what i did in attempt 1 with no luck. Hence the confusion.

ErgoloidMesylate - 12-5-2023 at 14:33

Eluent is 50/50 EtOAc hexane, first dot is ketone starting material, second dot is product and third is a cospot. This is from the first attempt, second is almost identical.

Setup used:

At a glance, the first one you are missing PEG, the second, the cesium.

You shouldn't be making dissociatives, as they shut the brain down.

The first one with peg, to ensure you can duplicate.

One of the papers I've linked managed to do it successfully with KOH instead of cesium carbonate, which according to them is better for this substrate

Which is what i did in attempt 1 with no luck. Hence the confusion.

It says less than 30, you ran it at 30.

BromicAcid - 12-5-2023 at 18:56

In this case the Green Chemistry paper involves a flow reaction. Flow reactions with their exceptional heat transfer and mixing together with the potential for high pressure and short residency times can do many things that traditional batch synthesis cannot. In this case they're running these reactions (depending on the example) between 5.2 and 32 Bar (75 and 365 PSIG) but in your case you seem to be running at atmospheric pressure (1 bar / 14 PSIG). So really it could give some guidance but not much.

The big thing is obviously the reagents, are you confident in their purities? Also, you've got the same Rf value for your starters and for your reactions, you'd expect the product to have a different Rf value, but do you have a known Rf value for your product with this solvent system or are you just looking for a change? I understand that you have other visual cues that are pointing to a failed reaction but the fact that you're not seeing any product makes me figure something somewhere is being missed.

ErgoloidMesylate - 12-5-2023 at 20:41

In this case the Green Chemistry paper involves a flow reaction. Flow reactions with their exceptional heat transfer and mixing together with the potential for high pressure and short residency times can do many things that traditional batch synthesis cannot. In this case they're running these reactions (depending on the example) between 5.2 and 32 Bar (75 and 365 PSIG) but in your case you seem to be running at atmospheric pressure (1 bar / 14 PSIG). So really it could give some guidance but not much.

The big thing is obviously the reagents, are you confident in their purities? Also, you've got the same Rf value for your starters and for your reactions, you'd expect the product to have a different Rf value, but do you have a known Rf value for your product with this solvent system or are you just looking for a change? I understand that you have other visual cues that are pointing to a failed reaction but the fact that you're not seeing any product makes me figure something somewhere is being missed.

The reaction he was doing seems to be from the second paper and here are the details of that reaction:

"The (2-
chlorophenyl) (cyclopentyl) methanone 2 (50.0 g, 0.24 mol), P(OEt)3 (59.8 g,
0.36 mol), ethanol (500 mL), and KOH (13.5g, 0.24mol) were added to a 1.0 L
three-necked flask under an atmosphere of oxygen in a balloon."

The reaction was run for 2 days, leading me to suggest he ran the reaction at too high a temp, perhaps the excess energy from the temperature was sufficient to undo any intermediate before it went to the desired molecule.

SplendidAcylation - 13-5-2023 at 04:13

It says less than 30, you ran it at 30.

It says "The mixture was stirred under 30°C for 48h."... I can see where you're coming from, but I interpret this to mean the "the mixture was stirred AT 30°C".

It seems like its comparable to saying "heating under reflux", the use of "under" being hard to pin down, but maybe it means something like "under the influence of"?

Perhaps someone could clarify the meaning of "stirred under 30°C"

arclightshroom - 13-5-2023 at 05:01

Looking for a change. The only reagent which purity can be debated is the ketone starting material, which is the only reagent not bought from a supplier. I think I'll either buy a standard to compare it with or find some service for analysis.

ErgoloidMesylate - 13-5-2023 at 09:54

Quote: Originally posted by SplendidAcylation

It says less than 30, you ran it at 30.

I interpret it as 'keeping it below 30'.

Sometimes certain papers don't give away all their tricks or secrets. This guy followed a procedure from a paper and presuming the paper actually works, looking for sources or causes of a non reaction. He wouldn't do what i suggest of either using the peg variation, or the cesium variation, which if it works at all should work, but since not, drop the temp to stay well under 30, possibly 15 or even in the fridge.

BromicAcid - 13-5-2023 at 12:46

Keeping it at 30°C or keeping it below 30°C, I can almost guarantee that's not going to cause a reaction to fail, maybe a slight loss of yield but not zero product.

ErgoloidMesylate - 13-5-2023 at 14:04

Keeping it at 30°C or keeping it below 30°C, I can almost guarantee that's not going to cause a reaction to fail, maybe a slight loss of yield but not zero product.

Almost guarantee is not air tight.
Energy can certainly unhook intermediates.
Will sulfuric dehydrate ethanol at 50?

Anhydride reactions, some of them won't work at too high a temp.

BromicAcid - 13-5-2023 at 18:43

Almost guarantee is not air tight.
Energy can certainly unhook intermediates.
Will sulfuric dehydrate ethanol at 50?

Anhydride reactions, some of them won't work at too high a temp.

You're ragging on the OP for +0.000000000000000000000000000000001°C. From what I can see you're arguing that 29.9999999999999 etc is fine but 30.000000000 is not. It's really blowing my mind. It would be interesting to see what ranges the OP actually had for the internal temperature of the reaction during the operations but the only information presented to us is 30°C bath.

Certainly 'almost guarantee' is not airtight. Just like every reaction is technically reversible - the application of chemistry is art after all, not science.

[Edited on 5/14/2023 by BromicAcid]

ErgoloidMesylate - 13-5-2023 at 19:36