Sciencemadness Discussion Board

Amination of tertiary alkyl halide

ctrade - 19-3-2013 at 13:19

I am trying to synthesize napthyl isopropylamine from napthyl isopropyl chloride but keep hitting walls. At first I thought of the Delepine reaction but it seems that tertiary alkyl halides will not react with hexamine.

Then I thought of slowly dripping napthyl isopropyl chloride into dilute ammonia but then I found that olefin formation is the dominant reaction with tertiary alkyl halide.

Any help would be appreciated.

[Edited on 19-3-2013 by ctrade]

Prometheus23 - 19-3-2013 at 13:34

Why do you keep saying tertiary alkyl halide? Isopropyl chloride is a secondary alkyl halide, not tertiary.

ctrade - 19-3-2013 at 13:54

Quote: Originally posted by Prometheus23  
Why do you keep saying tertiary alkyl halide? Isopropyl chloride is a secondary alkyl halide, not tertiary.


Napthylisopropyl chloride is a tertiary alkyl halide. Correct me if I'm wrong.

Nicodem - 20-3-2013 at 07:59

Quote: Originally posted by ctrade  
I am trying to synthesize napthyl isopropylamine from napthyl isopropyl chloride but keep hitting walls.

Can't you use starting materials more proper to the goal you want to achive? For example, if you start with 2-naphthyl-2-propanol you have several options for high yielding routes. But with 2-naphthyl-2-propyl chloride there is nothing really useful. SN1 alkylations NH3 in the form of liquid ammonia or ammonia solutions in inert solvents are known in the literature, but achieving yields above 10% is already a challenge.
Quote:
Then I thought of slowly dripping napthyl isopropyl chloride into dilute ammonia but then I found that olefin formation is the dominant reaction with tertiary alkyl halide.

That is what is supposed to occur. Anything else would be surprising. SN1 reactions on substrates where elimination is possible rarely ever work in neutral or basic media. Such substrates generally require acidic media.

Prometheus23 - 20-3-2013 at 10:27

First of all your original post simply said "isopropyl chloride" and "isopropylamine". You edited it to say "naphthylisopropyl chloride" and "naphthylisopropylamine" after I told you that you were wrong.

Second of all I doubt that Nicodem's advice will do you any good for two reaons:
1) I doubt you really comprehend what he's talking about.
2) I have a feeling you are actually trying to make 1-(2-naphthyl)propan-2-amine. Or "naphthylisopropylamine" as it's called on wikipedia. And you have just extrapolated "naphthylisopropyl chloride" from this name as a reasonable precursor.

ctrade - 20-3-2013 at 15:52

Quote: Originally posted by Nicodem  
Quote: Originally posted by ctrade  
I am trying to synthesize napthyl isopropylamine from napthyl isopropyl chloride but keep hitting walls.

Can't you use starting materials more proper to the goal you want to achive? For example, if you start with 2-naphthyl-2-propanol you have several options for high yielding routes. But with 2-naphthyl-2-propyl chloride there is nothing really useful. SN1 alkylations NH3 in the form of liquid ammonia or ammonia solutions in inert solvents are known in the literature, but achieving yields above 10% is already a challenge.
Quote:
Then I thought of slowly dripping napthyl isopropyl chloride into dilute ammonia but then I found that olefin formation is the dominant reaction with tertiary alkyl halide.

That is what is supposed to occur. Anything else would be surprising. SN1 reactions on substrates where elimination is possible rarely ever work in neutral or basic media. Such substrates generally require acidic media.



I am actually starting from 2-napthyl-2-propanol. Since making the chloride is so easy I thought it would be the best way to go.

Which high yielding methods are you talking about starting from the alcohol? Since it is tertiary I can't oxidise. Dehydration to alkene and then hydroamination?

Thanks for your response.

Forgot to add, near the middle of this page: http://www.chemguide.co.uk/mechanisms/nucsub/ammonia.html

It states that the reaction should occur without incident. I guess they don't take yield into consideration.



To the other guy - Yes I forgot to add that an aromatic group was attached so I added it before anyone had replied to my thread. I stated my end product. Please leave the thread.

[Edited on 20-3-2013 by ctrade]

[Edited on 20-3-2013 by ctrade]

bananaman - 20-3-2013 at 16:55

Since the mechanism is supposedly SN1, using a more polar solvent might help in reaction.

Nicodem - 21-3-2013 at 10:13

Quote: Originally posted by ctrade  
I am actually starting from 2-napthyl-2-propanol. Since making the chloride is so easy I thought it would be the best way to go.

I can't see the logic of your reasoning about the t-alkyl chloride. SN1 reactions of eliminable t-alkyl chlorides with basic nucleophiles are almost always good for nothing and are always the last choice for a synthetic strategy. Do you have any reference for a reaction of a similar alpha,alpha-dialkylbenzyl halide with ammonia? I may have seen a few, but they were pretty much useless yield-wise.
Quote:
Which high yielding methods are you talking about starting from the alcohol? Since it is tertiary I can't oxidise. Dehydration to alkene and then hydroamination?

Hydroamination would give you the wrong isomer. The simplest route from the alcohol is the classical SN1 reaction with a nitrile or HCN followed by the hydrolysis of the amide. The first reaction is traditionally called the Ritter reaction and is generally high yielding on t-alcohols. I would opt for the reaction with/in acetonitrile catalyzed by a few mol% of H2SO4, rather than use HCN, even though the formamide from HCN would be substantially easier to hydrolyze. With acetonitrile, the resulting N-t-alkyl acetamides are very difficult to hydrolyze, so the product from the reaction with acetonitrile might require harsh conditions such as KOH in ethylene glycol at 150 °C or a hydrazinolysis. Anyway, why don't you just check the literature and follow a published procedure for the synthesis of your amine? This is in my opinion the best you can do, unless you rapidly learn more chemistry and take the time to do some synthesis research (if you have enough of the substrate to afford this and access to the required analytical instruments). Yet, if all you need is to prepare the product, a day in the library will save you at least a week in the lab.
Quote:
Forgot to add, near the middle of this page: http://www.chemguide.co.uk/mechanisms/nucsub/ammonia.html

It states that the reaction should occur without incident. I guess they don't take yield into consideration.

It does not state anything about incidents - there is no mention of competing reactions, it only specifically shows the mechanism of the substitution and says nothing about the reaction outcomes. That page is not scientific as it has no references, it is just an educational page trying to explain simplified chemical mechanisms to pupils who are not yet to apply the knowledge gained. My suggestion is: stick to scientific reports, reviews and books, if you want to learn the art of chemistry. Educational texts are good for education, but they are not equally good for learning the art.
Quote:
To the other guy - Yes I forgot to add that an aromatic group was attached so I added it before anyone had replied to my thread. I stated my end product. Please leave the thread.

This is a public forum and thus you can not own a thread. All kind of people post here, some can judge you wrong, some don't, but as a new member you are inevitably subject to such accusations due to the annoying influx of wannabe drug cooks and kewls. You should not take this personally, as it does not have much to do with you specifically. Unfortunately, the only thing a new member can do, is to prove them wrong by contributing to the forum exchange of new ideas and knowledge. If you want respect, I can tell you that things will change immediately after you post some useful references and/or detailed experimental results.

ctrade - 22-3-2013 at 12:00

Thank you very much Nicodem. I have changed my original plan and will post it later. It will give me access to two products instead of just one (the original product in the first post) I'll post up the reaction scheme later tonight.

ctrade - 25-3-2013 at 11:54

I will do as advised and use either HCN generated in situ or acetonitrile with my alcohol. Ill post experimentals once complete.

I have another question related to this topic. Id like to synthesize neophylamine from neophyl chloride and hexamine. Since neophyl chloride is a primary alkyl halide it should react with hexamine but Im worried that the neopentyl effect will either slow the reaction down or stop it completely. I can find no references pertaining to this unique situation so it seems I am in uncharted waters.

Any advice from the gurus?

Nicodem - 25-3-2013 at 12:15

Quote: Originally posted by ctrade  
Id like to synthesize neophylamine from neophyl chloride and hexamine.

Forget it.

ctrade - 25-3-2013 at 22:01

Quote: Originally posted by Nicodem  
Quote: Originally posted by ctrade  
Id like to synthesize neophylamine from neophyl chloride and hexamine.

Forget it.


Thought so, it acts like a tertiary alkyl halide due to the neopentyl effect correct? So I guess the best way is to oxidize to neophyl alcohol followed by ritter reaction and hydrolysis like the substrate in the OP.

Neophyl chloride, magnesium turnings, and anhydrous ether stirred under a dry oxygen environment for 3 hours provides 70%+ yields of the alcohol. Ill post reference in the morning, its late.

ctrade - 27-3-2013 at 11:13

Finally tracked down some old Ritter references.

Here is an example from one of the papers:

N-t-Butylformamide:

To a mixture of 25ml acetic acid, 15g of t-butanol, and 11g of 90% sodium cyanide was added portionwise (over half-hour) and with shaking a solution of 50g concentrated sulfuric acid in 25ml acetic acid keeping the temperature at 50-60C. Vessel was stoppered and sat overnight. Reaction mixture was then poured into 500ml water, neutralized with 15% sodium hydroxide solution by dropwise addition with stirring and ice-cooling. The formamide is extracted with ether, dried over potassium carbonate, and ether is removed. 10g of amide is obtained after distillation with a boiling point of 202C.


I do not have any alkali cyanides on hand and would rather not make them but do have potassium ferrocyanide on hand. Is it possible to substitute this for sodium cyanide? I believe the sodium cyanide is only there to produce HCN and potassium ferrocyanide will do the same under the acidic conditions above. Left over aqueous solution will be added to bleach solution to destroy any HCN remaining.

I also found another paper using acetonitrile instead but like stated earlier hydrolysis of the amide could be problematic and due to the steric hinderance the acetonitrile might not react at all with my substrate (2-napthyl-2-propanol.)



[Edited on 27-3-2013 by ctrade]

Nicodem - 28-3-2013 at 09:43

Your knowledge of chemistry is indicative that you could have inappropriate lab experience, so unless you are desperately suicidal, don't use KCN or HCN when you can use acetonitrile instead!