Sciencemadness Discussion Board

Haloalkane synthesis help

UKnowNotWatUDo - 3-7-2010 at 00:23

This is my first post on this site, and after racking my brain for some time I thought maybe you all could give me a little insight on a project I'm working on. I do have a fair amount of knowledge and experience with organic chemistry, but I'm sure compared to some of you on this site I still have a lot to learn. I'm just looking for maybe a fresh thought or a new approach. The compound I'm looking to synthesize would be named (I believe):

2-(3-hydroxyphenyl)-1-phenyl-1-bromoethane

I think where I'm hitting a wall is either coupling a carbon-carbon bond and/or modifying an existing functional group like a carboxylic acid into a halogen (Hunsdiecker) without affecting the phenolic hydroxide. I have decent access to common reagents but would prefer not to work with Grignards simply because my friend has an odd aversion to ethers for god knows why. Again, any thoughts or suggestions would be appreciated. And any other really good sources for general information would also be great.

JohnWW - 3-7-2010 at 00:30

At some fairly early stage, the phenolic -OH group would have to be temporarily protected against the effects of subsequent reactions. This is commonly done by acetylation, with acetic anhydride or with glacial acetic acid plus a small amount of H2SO4. But that would be no protection against any strong reducing agents like LiAlH4 that can reduce esters, or against strong acids or alkalis that would prematurely hydrolyse the acetyl group.

Also, what is the problem with the ether or ethers used as solvents in Grignard reactions? It must be either their volatility especially of diethyl ether, in which case the Grignard solution in them could be handled in a ventilated fume cupboard or better still a glovebox; or the tendency of many of them to form explosive peroxides in the presence of oxygen, in which case they should be kept out of light and under nitrogen or argon, and handled in a glovebox under nitrogen or argon.

[Edited on 3-7-10 by JohnWW]

UKnowNotWatUDo - 3-7-2010 at 00:50

My original thought was to use a very strong base like potassium t-butoxide with acetophenone to form the enolate, and then in DMSO react it with 3-bromo/iodophenol. My thinking is that the nucleophilic carbon of the enolate would displace the halogen. However I'm not sure if this would proceed smoothly with the hydroxyl meta to the halogen leaving group. And even if it did would there be a reaction you know of that would turn the carbonyl into a halogen on the ethyl chain?

DJF90 - 3-7-2010 at 03:13

I don't understand why you "would prefer not to work with Grignards simply because my friend has an odd aversion to ethers for god knows why" - it's got nothing to do with your friend; you're the one doing the synthesis. Allowing the use of grignard reagents, here's your route:

>Nitrobenzene to m-bromonitrobenzene (http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv1...)
>Formation of grignard reagent (standard procedure - see any practical textbook)
>Reaction with styrene oxide (Can be made by epoxidation of styrene)
>Reduction of the nitro group, diazotisation and hydrolysis to yield the phenol (again, standard reaction)
>Reaction of the benzyl alcohol to form the benzyl bromide - pick from a number of methods, simplest would be stirring with aqeuous HBr.

You cannot perform an Sn2 reaction on an aryl halide. The closest to that is the SnAr mechanism, but you do not have sufficiently electron withdrawing groups present. A nitro group in the ortho/para position would work - that wouldn't give you the right compound though.

I suspect a similar pathway could be followed using acetophenone as the precursor, instead of nitrobenzene. Bromination using Br2/AlCl3 gives the m-bromoacetophenone, which can be used to form the grignard and react with styrene oxide. The benzyl alcohol can be protected with acetic anhydride, and a Baeyer Villiger oxidation produces an acetate from the acetophenone.

The two acetates can then be hydrolysed to the benzyl alcohol and the phenol, and the benzyl alcohol can be brominated as before (I suspect the benzyl bromide, if formed before the oxidation instead of protection with acetic anhydride, would be hydrolysed back to the alcohol under the conditions for ester cleavage).

[Edited on 3-7-2010 by DJF90]

UKnowNotWatUDo - 3-7-2010 at 19:35

I mentioned my friend's aversion to ethers because he is also my roommate and I'm trying to respect his wishes. Hence why I requested no methods that involve Grignards.

Barium - 4-7-2010 at 04:37

Quote: Originally posted by UKnowNotWatUDo  
I have decent access to common reagents but would prefer not to work with Grignards simply because my friend has an odd aversion to ethers for god knows why.

I can very well understand your friends view on ethers, especially if he's had a nasty encounter with their peroxide-forming capabilities. A way safer alternative than the commonly used ethers are the glymes (glycol ethers). Beside being easier to dry they are also more stable than THF, diethyl ether and diisopropyl ether and many reaction rates are higher in them as well.

densest - 4-7-2010 at 12:54

Perhaps off topic, but how does one dry glymes? They are all miscible with water (at least a few percent) and many absorb water from the air... do the usual inexpensive drying agents (anhydrous MgSO4, for instance) work well enough that the last traces can be removed with a few shreds of Na or something like it? I'd be reluctant to use highly acidic or basic agents to remove most of the water.

UKnowNotWatUDo - 7-7-2010 at 07:07

Wait, DJF90, you mentioned that you didn't think it was possible to use an enolate ion to perform a substitution reaction with a halobenzene. But i found an article that seems to suggest that you can. Unless I am missing something, which is definitely possible. Here is the reference for the article.

J. Org. Chem., 1977, 42 (8), pp 1449–1457

Nicodem - 7-7-2010 at 08:48

Quote: Originally posted by UKnowNotWatUDo  
This is my first post on this site, and after racking my brain for some time I thought maybe you all could give me a little insight on a project I'm working on.

I think you should read this thread and meditate upon it.
Quote:
I do have a fair amount of knowledge and experience with organic chemistry, but I'm sure compared to some of you on this site I still have a lot to learn. I'm just looking for maybe a fresh thought or a new approach. The compound I'm looking to synthesize would be named (I believe):

2-(3-hydroxyphenyl)-1-phenyl-1-bromoethane

If you had at least a minimum of "knowledge and experience with organic chemistry" you would have realized that you are not "looking to synthesize" 2-(3-hydroxyphenyl)-1-phenyl-1-bromoethane, because it would be totally useless for what you are up to. What you are after is either alpha-(meta-hydroxyphenyl)acetophenone or 2-(3-methoxyphenyl)-1-phenylethylamine. You would have realized that already if you would have done the minimum necessary before opening this thread: to search the literature!
Quote:
Again, any thoughts or suggestions would be appreciated. And any other really good sources for general information would also be great.

My suggestion is to start realistically instead of fantasizing about things that are not accessible to you. Find yourself another target, one better suited to your knowledge and skills (or lack thereof) and build your knowledge and skills from there on. Or else give up organic chemistry now and find yourself another hobby. That is what you will do later on anyway, unless you listen to my advice.
Scientific libraries are an excellent source for general information.

UKnowNotWatUDo - 7-7-2010 at 10:07

Your rather rude nature aside, you are also completely wrong. Neither of the compounds you listed are what I am looking for and I'm not even sure why you think they are. And I don't really care if you think I'm stupid or not cut out for chemistry or I haven't provided enough references or research, because I know exactly what I did. I wasn't looking to be spoonfed anything, I had taken my own knowledge as far as I could and then asked for some input from others. If you want to make it out like I'm an idiot who knows nothing and should give up now because YOU are just sooo much better than me, that's fine. I respect that you are smart and know what you're talking about around here. But I put a question out there and invited anyone who had any interesting thoughts to comment and put in their two cents, that's all. I'm not nearly as intense into this whole hobby as a lot of you, and maybe I will be in the future and maybe I won't. I don't really care. Sorry if I broke some "unwritten rules" you mods like to follow, but I'm new and now I know. If that was your only beef with me then that's fine. I apologize. But there's no need to completely degrade me when you really have no idea about me except one little post. You may be good at organic chemistry, and you may be a "super moderator" on a site, but you don't HAVE to be a dick to people you don't even know.

watson.fawkes - 7-7-2010 at 11:23

Quote: Originally posted by UKnowNotWatUDo  
Neither of the compounds you listed are what I am looking for and I'm not even sure why you think they are.
I can answer that one. It's because at this stage of conversation your behavior is indistinguishable from the many semi-competent aspiring drug cooks that show up here for a day or two and then leave. If you'd like to make yourself distinguishable, there are many options, two of the quickest being (1) posting the results of your literature search and (2) full and complete disclosure about your goals, starting points, methods, and motivations.

UKnowNotWatUDo - 7-7-2010 at 20:12

I guess I can understand that. But I'm not the most organized person and not all of my research has been in literature. Partly because some of it is over my head and it's a little easier for me to read through this site and get a better understanding. But also partly because being new to this whole online amateur chemistry thing (but not chemistry in general, just online and on sites like this) I don't know too many places to look or even what I'm looking for. I just look around until I find something that interests me. And as far as the drug cook thing, like I said, I guess I can understand that. But I honestly can't even think of a single drug that has that same structure or even the structure of the compounds that Nicodem listed. I'm not really in on the whole drug chemistry thing too much, so I'm sure I just missed one and you guys all think it's obvious.

watson.fawkes - 7-7-2010 at 20:36

Quote: Originally posted by UKnowNotWatUDo  
Partly because some of it is over my head and it's a little easier for me to read through this site and get a better understanding.
OK. Start there. Tell us all why you're interesting in that compound, what led you there, and what you'd do with it if you had some. Post URL's for what you have read, even if they're not academic. Tell us a bit of your autobiography with respect to this structure.

As for the general principle, to anyone coming afterward, I offer the following.

UKnowNotWatUDo - 7-7-2010 at 20:43

To be honest it only seems like I'm going to meet more disrespect and condescending comments, which doesn't exactly encourage me to start spilling all about myself and what I was thinking and planning. If you can honestly tell me there's a drug that I could easily "cook" from the compound I am talking about, I'll be a little more inclined to discuss my thoughts. Because I'll understand where you are coming from. But right now it just sounds like you guys have had too many experiences with drug cooks and people not as smart as you, and you automatically shun whoever you get a funny feeling about. And if it takes me telling all of you all about myself to make your suspicions go away, then I think I'd rather just go back to reading on this site and not posting. Which is what over half of the members here do anyways.

jon - 7-7-2010 at 21:31

sorry to but in.
but not everyone who synthesizes pharmacologically active compounds are recipe cooks.
some are laid off professionals who said to hell with corporate america.
and others are just doing it out of sheer curiosity.
and some are incompetent would be chemists,
but not everyone who makes "drugs" are dipshit knownothings.
not that jon would ever consider anything as despicable as resorting to the drug trade there are plenty of high paying jobs after all.:D


[Edited on 8-7-2010 by jon]

497 - 7-7-2010 at 22:34

UKnowNotWatUDo- I think you should forgive Nicodem's harsh reaction.. He has to deal with a lot of punks who don't care about chemistry for anything more than to make a buck.. Your post was made in a very similar style to theirs and had many markers of the "drug cook," which made it easy to jump to that conclusion. But I think he was mistaken.. After further posting and investigation it seems clear that you're not a drug cook. I think if you give the forum a chance you will find it very welcoming. Some further clarification on the goal would help dispel any lingering suspicions of drug cookery.

jon- Nobody said all people who synthesize pharmacologically active compounds are drug cooks, and I don't think many people on the forum think so. But when they come around displaying no interest in chemistry and only greed, it's not surprising that they get a negative reaction.. And after dealing with so many of them, I think it gets to be a reflex for the mods, understandably.

[Edited on 8-7-2010 by 497]

jon - 8-7-2010 at 06:27

497 i understand your point that shit does get old.
myself i like to invent new things that may have some activity that's a cool hobby does'nt have much to do with greed.
besides all you get from dealing drugs is killed or locked up.

UKnowNotWatUDo - 8-7-2010 at 06:38

Thanks guys. It's good to know not everyone thinks quite the same way. I guess to stay on topic I do have a question. Given the reference I posted earlier about using an enolate and a halobenzene in DMSO to form a carbon-carbon bond, I could in theory form alpha-(meta-hydroxyphenyl)acetophenone (given the enolate was from acetophenone and the halobenzene was actually 3-bromophenol). Is there a reaction to transform a carbonyl into a halogen? This would, I believe, yield the desired product. However the only way I could think of to do this would be to reduce the carbonyl to an alcohol and then transform the alcohol into a halogen using something like HBr?

Quantum_Dom - 6-9-2010 at 10:30

Quote: Originally posted by jon  
sorry to but in.
but not everyone who synthesizes pharmacologically active compounds are recipe cooks.
some are laid off professionals who said to hell with corporate america.
and others are just doing it out of sheer curiosity.
and some are incompetent would be chemists,
but not everyone who makes "drugs" are dipshit knownothings.
not that jon would ever consider anything as despicable as resorting to the drug trade there are plenty of high paying jobs after all.:D


[Edited on 8-7-2010 by jon]


jon is dropping the reason over hysteria here ! well done !


......wait what ? :D

Anders2 - 16-9-2010 at 18:12

I might be able to provide a suggestion. I read somewhere that heating toluene and CH2O can form CH3(C6H4)CH2OH, where I think the methyl and aldehyde groups are next to eachother.

(C6H5)CH2CH=O is not an uncommon regent, but I forgot what it is called, I think it might be Phenylacetaldehyde.

This could be heated with 3-hydroxyphenol, possibly forming
2-(3-hydroxyphenyl)-1-phenyl-1-hydroxyethane, in a similar reaction to the one described above.

A completely separate route might be:
3-acetate-Phenylacetaldehyde plus phenylmagnesium bromide, followed by workup with aqueous acid, then treatment with NH4OH to hydrolyze off the acetate.

AcOC6H5-CH2-CH=O + C6H5-MgBr ===>
C6H5-CH2-CH(OH)-C6H5

Using NaBr and anhydrous H3PO4, could likely replace the hydroxyl group on the ethane with a bromine.

The hydroxyl group on the ethane, rather than on the phenyl, would be the first to be replaced, since the phenyl is somewhat more electron withdrawing. You could probably get a decent yeild with this, but would of course have to verify this suggestion by doing a little research.

What I meant by "3-acetate-Phenylacetaldehyde" is a synomnym for 3-acetyldehyde-phenol acetate ester, I cannot think of the proper name.


[Edited on 17-9-2010 by Anders2]

[Edited on 17-9-2010 by Anders2]

madscientist - 16-9-2010 at 18:27

You're thinking of Blanc chloromethylation, which will yield equal proportions of the ortho and para product, PhCH2Cl.

The aldehyde you mention is not something that will fall into your hands easily. It's a mere oxidation away from phenylacetic acid, a precursor to amphetamines, and so is surely watched by the DEA. Buy it and you may find yourself in a jail cell - possession of a precursor, particularly to amphetamines, is a serious charge.

Anders2 - 16-9-2010 at 18:44

"The aldehyde you mention is not something that will fall into your hands easily. It's a mere oxidation away from phenylacetic acid"

Oh, in that case it is easy!
React Br2 with AcOH, forming bromoacetic acid, then form the an ester (with ethanol for example), then react with phenyl magnesium, now forming PhCH2C(=O)OEt. Hydrolyze with a base, then Zn/HCl (or something milder for better yield) will form PhCH2CH2OH, then prepare the aldehyde from this.

Sorry, most of this is a little speculative.



[Edited on 17-9-2010 by Anders2]

DDTea - 16-9-2010 at 19:02

Quote: Originally posted by Anders2  
"The aldehyde you mention is not something that will fall into your hands easily. It's a mere oxidation away from phenylacetic acid"

Oh, in that case it is easy!
React Br2 with AcOH, forming bromoacetic acid, then form the an ester (with ethanol for example), then react with phenyl magnesium, now forming PhCH2C(=O)OEt. Hydrolyze with a base, then Zn/HCl (or something milder for better yield) will form PhCH2CH2OH, then prepare the aldehyde from this.

Sorry, most of this is a little speculative.



[Edited on 17-9-2010 by Anders2]


I guess "speculative" is one way to put it. This won't work out the way you're thinking.

[EDIT] whoops, that was a goof. Grignard reaction with esters results in a tertiary alcohol + a primary alcohol, not a ketone.

[Edited on 9-17-10 by DDTea]

madscientist - 16-9-2010 at 19:07

The proposed reaction with the given conditions won't yield the product you have in mind. The primary reaction will be with the carbonyl on the ester to yield a tertiary alcohol. Any coupling that occurs is likely to be followed by alkylation of the carbonyl present on the newly formed phenylacetate ester.

However, coupling is possible under different conditions. The key is to use the salt of the carboxylic acid, and not the ester. This avoids the alkylation of the carbonyl. A catalyst is also necessary: Li2CuCl4.

Reference: http://www.jlr.org/content/23/1/197.full.pdf

Reduction of carboxylic acids is not trivial and few reducing agents can achieve it. Zn/HCl surely is not up to the task. LiAlH4 will reduce them to the alcohol. I know there are ways to reduce directly to the aldehyde but I can't remember them offhand.

Anders2 - 16-9-2010 at 19:15

Perhaps you meant PhCH2C(=O)CH2CH3 would result?

Now I am getting a little desperate, but perhaps react this with a limited quantity of SeO2, forming PhCH2C(=O)CH(=O)CH3,
then oxidize with H2O2, forming the desired product, in a reaction like that used in glow sticks.

Or anhydrous NH3 can react/dehydrate with esters, replacing the linking oxgen. --C(=O)NHCH2-- There was a picture in the German wikipedia that showed 4-hydroxy pyridine resulting from
the corresponding ether that lacked any nitrogen atoms, there is a picture on my site somewhere. This then should be protected form reduction, and can later be hydrolyzed with a base to the carboxyl salt, potentially allowing PhMg to be workable.

The (=O) could be preemptively protected by condensation to the imine, using analine. This can easily be hydrolyzed back off later, after the PhMg is gone.

Al/Hg amalgam might be suitable to reduce a carboxyl, sorry my mistake, of course HCl/Zn is not strong enough.

[Edited on 17-9-2010 by Anders2]

madscientist - 16-9-2010 at 19:22

Quote:
Perhaps you meant PhCH2C(=O)CH2CH3 would result?


Nope.
Quote:
Or anhydrous NH3 can react/dehydrate with esters, replacing the linking oxgen. --C(=O)NHCH2--


RCOOR' + NH3 ----> RCONH2 + R'OH

Anders2 - 16-9-2010 at 19:25

Okay then,
What about acetic acid, condense with Analine to form the imine, CH3C(=NPh)NH(Ph), then react with Br2 using an oil soluble acid to form the C=C double bonded tautomer, then reduce the sensitive N--Br back to NH, now use this:
BrCH2C(=NPh)NHPh to couple with PhMg ?

Those protective analines can be gotten rid off after

about that last one,
RCONH2 HOCH2R
you are probably correct, but that should not matter,
the RCONH2 can still be hydrolyze to the carboxyl salt with a base.

[Edited on 17-9-2010 by Anders2]

DDTea - 16-9-2010 at 19:40

Quote: Originally posted by Anders2  
Okay then,
What about acetic acid, condense with Analine to form the imine, CH3C(=NPh)NH(Ph), then react with Br2 using an oil soluble acid to form the C=C double bonded tautomer, then reduce the sensitive N--Br back to NH, now use this:
BrCH2C(=NPh)NHPh to couple with PhMg ?

Those protective analines can be gotten rid off after

about that last one,
RCONH2 HOCH2R
you are probably correct, but that should not matter,
the RCONH2 can still be hydrolyze to the carboxyl salt with a base.

[Edited on 17-9-2010 by Anders2]


Look at the mechanism for formation of a Schiff base. That lone pair is required to form the carbinolamine. When you've got an acid (acetic acid here) and a base (aniline here), the first--and fastest--reaction is going to be a proton transfer, which means the Nitrogen's lone pair is no longer free to react with the carbonyl. As such, this only really works with aldehydes and ketones.

Amide formation from carboxylic acids and amines also gives low yields--the equilibrium is pretty unfavorable here.

In Organic Chem, it's as important to know when something *won't* happen as it is to know when something *will* happen.

[Edited on 9-17-10 by DDTea]

Anders2 - 17-9-2010 at 13:51

I obviously agree with everything above, I just thought the process would go without saying, so I did not elaborate.

Obviously RCOOH would have to be made to first condense with analine. RCONH(Ph) ,analogous to condensation of amino acids. (or SCl2 could be used to form RCOCl which could then condense with an amine)

Then the condensation to the imine (with another PhNH2)would would be carried out under strongly basic conditions.

RCONH(Ph) + H2N(Ph) ==KOH==> RC(=NPh)NH(Ph) + H2O