[ccyx]

I tried the following reaction but didn't get any product, HNMR showed no reaction at all.I have found some examples on Reaxys, and tried the same contidions (DCM 25℃), but can't work.I also find some reaction like it (on reaxys) and use DMAP or Et₃N as catalyst but got nothing.

I also tried heating or ice bathing conditions, but it didn't work either.

I doubt that they can react and that the product can be stable at room temperature. I also want to know the mechanism in this reaction.



nmr of products: 1H NMR (300 MHz, DMSO) δ 10.53(s, 1H ), 3.32(s water), 2.90(s, 4H), 2.59(s, 4H). The eq. is NHS:SA = 1:1.

I am a newr in this forum and this is my first topic, i have read the form rules, but i'm not sure if there something wrong . Thank you all for your responses.

[rolnor]

Interesting! Did you run the reaction in the NMR tube? Workup can destroy the product. Have you reference NMR? Did you run the reaction exactly as they did in the Reaxys papers?

[Babcock_Hall]

Rolnor made a valuable point.  One philosophy of trying new chemistry is to isolate the reaction from the work-up, and from the purification.  In other words, one wants to be certain that the reaction provided the correct crude product first.  Then if the crude product is lost after work-up, one knows where the problem is.  We think that we have lost the product during a column purification in at least one instance.

[ccyx]

Interesting! Did you run the reaction in the NMR tube? Workup can destroy the product. Have you reference NMR? Did you run the reaction exactly as they did in the Reaxys papers?

No,  I carried out the reaction in a 50 ml round-bottom flask, and then distilled  at 40°C to obtain a white powder. The white powder was then dissolved in DMSO-d₆ for proton NMR spectroscopy.I compared the proton NMR spectra of NHS and SA in the database and found that there may be no reaction at all. The chemical shift of the OH group in NHS is around 10.5, while the COOH group should be around 12. In the literature, the reaction is carried out by mixing the reagents in an ice bath and then to room temperature. I did not use an ice bath in my procedure, but other than that, the method was the same.

[ccyx]

Rolnor made a valuable point.  One philosophy of trying new chemistry is to isolate the reaction from the work-up, and from the purification.  In other words, one wants to be certain that the reaction provided the correct crude product first.  Then if the crude product is lost after work-up, one knows where the problem is.  We think that we have lost the product during a column purification in at least one instance.

I used TLC monitoring with petroleum ether and ethyl acetate(add some HAc) as the developing solvent, but no new spots appeared. At the end of the reaction (after 5 hours), I obtained a solid using a rotary evaporator and performed HNMR analysis without silica gel purification. Therefore, it is highly likely that there was no reaction. If the product had decomposed, it would have likely formed glutaric acid instead of glutaric anhydride, correct?

I have tried this reaction many times.The reaction conditions are below:

SA:NHS	Solvent	Catalyst	Temperature	Reaction Time	Result
1:01	DCM	None	Room Temperature	Overnight	No reaction
1:01	DCM	None	40°C	14 h	No reaction
1:01	DCM	TEA	Room Temperature	5 h	No reaction
1:01	DCM	TEA	40°C	10 h	No reaction
1:01	DCM	None	0°C	5 h	No reaction
1:01	DCM	DMAP	Room Temperature	5 h	No reaction
1:01	THF	None	Room Temperature	Overnight	No reaction
1:01	DMF	None	Room Temperature	5 h	No reaction
1:01	DMF	DMAP	100°C	14 h	No reaction
2:01	DCM	None	Room Temperature	Overnight	No reaction

[rolnor]

OK, its surprising. A published procedure normally works. Have you contacted the authors of the paper?

[Babcock_Hall]

https://organicchemistrydata.org/hansreich/resources/nmr/?page=05-hmr-02-delta%2F#05-hmr-02-delta-OH
I was confused by your mentioning glutaric acid, which has 5 carbon atoms.

I may not be understanding which signals you are using to judge whether or not you formed the product, but you mentioned the carboxylic acid and hydroxyl hydrogens.  In my limited experience the chemical shift of a carboxylic acid hydrogen depends on the presence of other exchangeable hydrogens that are present.  That having been said, one of the shifts that you reported above for non-exchangeable hydrogen atoms is consistent with what is reported for succinic anhydride (2.90 ppm in DMSO).  N-hydroxysuccinimide is reported to be 2.79 ppm in D₂O, but I am not sure about where it appears in DMSO.  I agree that your NMR data are not consistent with the desired product.

[ccyx]

OK, its surprising. A published procedure normally works. Have you contacted the authors of the paper?

That's a good idea! The literature I found is from a patent that doesn't provide contact information, but I think that I can try searching for the author's email online. I'll try it.

[rolnor]

OK, patents can actually be nonsense...

[ccyx]

https://organicchemistrydata.org/hansreich/resources/nmr/?page=05-hmr-02-delta%2F#05-hmr-02-delta-OH
I was confused by your mentioning glutaric acid, which has 5 carbon atoms.

I may not be understanding which signals you are using to judge whether or not you formed the product, but you mentioned the carboxylic acid and hydroxyl hydrogens.  In my limited experience the chemical shift of a carboxylic acid hydrogen depends on the presence of other exchangeable hydrogens that are present.  That having been said, one of the shifts that you reported above for non-exchangeable hydrogen atoms is consistent with what is reported for succinic anhydride (2.90 ppm in DMSO).  N-hydroxysuccinimide is reported to be 2.79 ppm in D₂O, but I am not sure about where it appears in DMSO.  I agree that your NMR data are not consistent with the desired product.

It' my fault.The anhydide is succinic anhydide. I use succinic acid as comparison. Its active hydrogen's chemical shift in DMSO-d6 is about 12.5,and the chemical shift of the hydrogen on the methylene group is about 2.5. I think if the reaction succeed, the chemical shift of methylene group may be different.

I am currently attempting to react glutaric acid with NHS using DCC as a catalyst, which should yield a portion of the desired product.

[Babcock_Hall]

This may be a quibble, but DCC is a reactant, as opposed to a catalyst.  DMAP is a possible catalyst.

[clarkstill]

Have you checked the purity of your starting materials? As you say, this reaction is well-precedented in the literature (e.g. i found Anal. Chem. 2015, 87, 21, 11048, where the reagents are sonicated, without any exogenous base required). The reaction (both the anhydride SM and ester product) may be sensitive to moisture: are you drying your DCM?

Can you post NMRs of your starting material and crude reaction mixture? The data from the paper above are in CDCl3, but if you have literature values in DMSO then that's fine too.

[rolnor]

https://organicchemistrydata.org/hansreich/resources/nmr/?page=05-hmr-02-delta%2F#05-hmr-02-delta-OH
I was confused by your mentioning glutaric acid, which has 5 carbon atoms.

I may not be understanding which signals you are using to judge whether or not you formed the product, but you mentioned the carboxylic acid and hydroxyl hydrogens.  In my limited experience the chemical shift of a carboxylic acid hydrogen depends on the presence of other exchangeable hydrogens that are present.  That having been said, one of the shifts that you reported above for non-exchangeable hydrogen atoms is consistent with what is reported for succinic anhydride (2.90 ppm in DMSO).  N-hydroxysuccinimide is reported to be 2.79 ppm in D₂O, but I am not sure about where it appears in DMSO.  I agree that your NMR data are not consistent with the desired product.

It' my fault.The anhydide is succinic anhydide. I use succinic acid as comparison. Its active hydrogen's chemical shift in DMSO-d6 is about 12.5,and the chemical shift of the hydrogen on the methylene group is about 2.5. I think if the reaction succeed, the chemical shift of methylene group may be different.

I am currently attempting to react glutaric acid with NHS using DCC as a catalyst, which should yield a portion of the desired product.

DCC is not the correct reagent in this reaction, you need a nucleophilic catalyst, DCC is not used this way. But I am happy for you, the reaction has probably worked, GREAT!