Sciencemadness Discussion Board

Preparing Grignard Reagents from 3-Bromopropylamine hydrobromide and other Compounds

VSEPR_VOID - 11-8-2018 at 17:31

I have taken on a recent project for school that involves preparing a grignard reagent that would allow for the addition of a primary amine or carboxyl group to a molecule.

I have selected 3-Bromopropylamine hydrobromide (1), 2-Chloroacetamide (2), and maybe 4-Iodobutyric acid (3).

Has anyone had any problems preparing grignard reagents that contain amine or carboxyl groups?

1. (https://www.sigmaaldrich.com/catalog/search?term=MFCD0001291...)

2. https://www.sigmaaldrich.com/catalog/search?term=MFCD0000802...

3. https://www.sigmaaldrich.com/catalog/search?term=MFCD0001585...

[Edited on 12-8-2018 by VSEPR_VOID]

clearly_not_atara - 11-8-2018 at 17:48

Grignards react with carboxyl groups including amides. Preparing the Grignard of 3-bromopropylamine hydrobromide might be possible if you first basify it in a nonpolar solvent so it doesn't cyclize. Cyclization should be slow because 4-membered rings are not favorable.

Bowever, I'm not sure you've interpreted the instructions correctly. All Grignards can be carboxylated by rxn with carbon dioxide. Rxn of organomagnesium with imines gives an amine. Are you sure these aren't the intended reactions?

VSEPR_VOID - 11-8-2018 at 18:47

I am trying to prepare grignard reactions that will react with C60 to give products that terminate in a amine or carboxyl group.

Would it be possible to protect the amine groups with Boc? I know that will not work with the carboxylic acid groups as butyl alcohol is the protecting groups and esters react with grignard reagents.

DraconicAcid - 11-8-2018 at 19:03

I think the Grignard would deprotonate the amine, wouldn't it?

clearly_not_atara - 11-8-2018 at 19:14

The carboxyl group can be protected as an orthoester. For the amine it is harder. N,N-dibenzyl is a possibility. BOC is runnin in the wrong direction.

VSEPR_VOID - 11-8-2018 at 22:27

I will have to change my plan.

What about :

Reaction of CH2=CHCH2MgCl with C60

Anti syn addition with BH3-THF

Oxidation to carboxylic acid with KMnO4

Acid work up

esterification with Boc-3-Amino-1-propanol to give the final product terminating in a primary amine

One potential issue: Potentially hydrating the C60 cage (which would be unwanted)



Alternatively:
Reaction of CH2=CHCH2MgCl with C60

Anti syn addition with BH3-THF

Form an ether with 3-Amino-1-propanol

Sigmatropic - 12-8-2018 at 01:25

Amines can be protected as the Stabase adduct for use with gringards.
http://reag.paperplane.io/00000233.htm
http://reag.paperplane.io/00000259.htm
Acids as ortho esters (https://www.sciencedirect.com/science/article/pii/S004040390...) or as oxazolines (https://pubs.acs.org/doi/abs/10.1021/jo00932a024).

CuReUS - 12-8-2018 at 03:13

Quote: Originally posted by VSEPR_VOID  
What about :
Reaction of CH2=CHCH2MgCl with C60...
This is a good idea,since it eliminates the need for protecting groups as well as leaves room for furthur FGI's.
I recently thought of a way to make acids from alkenes using bleach which could be applied here.Treating the alkene with bleach would give a halohydrin,which would get oxidised to ketone by the remaining bleach and then undergo a favorskii rearrangement in the basic bleach medium to give an acid.

As for making amines,you can hydroaminate the alkene

VSEPR_VOID - 12-8-2018 at 16:41

Quote: Originally posted by CuReUS  
Quote: Originally posted by VSEPR_VOID  
What about :
Reaction of CH2=CHCH2MgCl with C60...
This is a good idea,since it eliminates the need for protecting groups as well as leaves room for furthur FGI's.
I recently thought of a way to make acids from alkenes using bleach which could be applied here.Treating the alkene with bleach would give a halohydrin,which would get oxidised to ketone by the remaining bleach and then undergo a favorskii rearrangement in the basic bleach medium to give an acid.

As for making amines,you can hydroaminate the alkene


Do you have any publications or articles relating to either of those ideas? I protocol?

CuReUS - 13-8-2018 at 03:47

Quote: Originally posted by VSEPR_VOID  
Do you have any publications or articles relating to either of those ideas? I protocol?

my alkene to acid idea is basically a combination of 3 well known reactions in one pot - synthesis of halohydrins, steven's oxidation and the favorskii rearrangement.Since its just an idea,I don't have any refs to back it up.

alternatively,you could convert the alkene to epoxide and make it undergo a meinwald rearrangement to aldehyde,which could further be oxidised to acid-https://pubs.rsc.org/en/content/articlehtml/2015/cc/c4cc0715...

As for the hydroamination -https://en.wikipedia.org/wiki/Hydroamination

DJF90 - 13-8-2018 at 11:23

Assuming the C60 reacts with the grignard but is stable to the subsequent manipulations (fullerene chemistry is not my forte), why not use allylmagnesium bromide and the oxidatively cleave the alkene to the aldehyde or acid (depending on which you'd prefer/require. You'd obviously lose a carbon by doing this (C3 to C2 derivatives) but if chain length is not a specific requirement then it should be fine.

See https://en.m.wikipedia.org/wiki/Lemieux–Johnson_oxidation for details on the oxidative cleavage. There is an alternative that replaces OsO4 with RuCl3 or KMnO4 to the same effect. Theres also the potential to use ozone.

Again, the caveat to all this is that the fullerene is stable to the oxidative conditions required to functionalise the allylated-C60

VSEPR_VOID - 13-8-2018 at 13:00

Fullerene chemistry is a relativly new field (from about the mid 1980 to now) but their reactions with nucleophiles, such as grignard reagents, are well documented. I will attach a paper that is a general overview.

[Edited on 13-8-2018 by VSEPR_VOID]

Attachment: Review of Reactions of Fullerenes.pdf (900kB)
This file has been downloaded 392 times

Attachment: Addition Reactions of Buckminsterfullerene.pdf (1.4MB)
This file has been downloaded 405 times

[Edited on 14-8-2018 by VSEPR_VOID]