Sciencemadness Discussion Board

substitution of alkyl halide with NaOH

Dr.Q - 14-8-2013 at 01:30

In theory an alkyl halide give substitution with a strong base such as NaOH or CH3ONa etc. For example i want to convert my alkyl halide , let say its bromobuthane , in to an alchohol with NaOH.

In theory a substitution is possibble but in expirement a little problem came in to my mind. NaOH is not soluble neither in bromobuthane nor any other alcohol . How will the reaction going ? How can make the substitution possible



[Edited on 14-8-2013 by Myeou]

[Edited on 14-8-2013 by Myeou]

Dany - 14-8-2013 at 03:31

Hello Myeou,

what are you going to do is a classical bimolecular nucleophilic substitution SN2. although the reactant are in separate phase the reaction can be accomplished at the interface. make a solution of sodium hydroxide and try to heat the mixture with the alkyl bromide with vigourous stiring. use for example acetone for your organic bromide because acetone favors SN2. the sodium iodide formed will be dissolved in aqueuous phase. you can test the iodide formed in the aqueuous phase by oxidizing I- to I2 using H2O2.

Dany.

[Edited on 14-8-2013 by Dany]

Nicodem - 14-8-2013 at 07:52

Quote: Originally posted by Myeou  
In theory an alkyl halide give substitution with a strong base such as NaOH or CH3ONa etc. For example i want to convert my alkyl halide , let say its bromobuthane , in to an alchohol with NaOH.

I don't know which theory you refer to, but the theory of SN2 and E2 mechanisms say that the reaction of 1-bromobutane with NaOH would give 1-butene, 1-butanol and dibutyl ether as the expected products. Their ratio would depend on the reaction conditions, but using NaOH is unlikely to give 1-butanol as the main product under any non-elaborate conditions.
2-Bromobutane or any of the bromoisobutanes would give other products. The simplest would be the reaction of t-butyl bromide with NaOH which would be expected to give isobutene almost exclusively. All the others would give unfavorable mixtures.
Quote:
NaOH is not soluble neither in bromobuthane nor any other alcohol . How will the reaction going ? How can make the substitution possible

That is one of the reasons why solvents are used in chemistry. Primary and secondary alcohols are obviously not suitable solvents for this reaction as they would react with 1-bromobutane themselves.

Anyway, if the desired product is 1-butanol, the reaction of 1-bromobutane with NaOH is of little to no use. Such a transformation would be more reasonably done by the reaction of 1-bromobutane with potassium acetate followed by hydrolysis. See examples in the literature.

Dany - 14-8-2013 at 10:13

As the leaving group present is a bromide ion i thing that the hydroxide ion will react fast with alkyl bromide to form the alcohol, while the elimination product will be predominant with the alkyl chloride. of course with no much heating the reaction will be an SN2 to form any alcohol.

i dont think that the acetate anion will react by an SN2 to form the ester since it is a very weak nucleophile.

Dany.

Nicodem - 20-8-2013 at 08:15

Quote: Originally posted by Dany  
i dont think that the acetate anion will react by an SN2 to form the ester since it is a very weak nucleophile.


Just two examples of the many that can be found in the literature:

CH3COOK and BuBr in PEG, 90% yield of butyl acetate (DOI: 10.1016/S0040-4039(01)86654-5)

CH3COOK and BuBr, 1 mol% Bu4NBr, 2 h at 60 °C, solventless, 98% yield of butyl acetate (DOI: 10.1016/S0040-4020(01)91977-5)

The acetate anion is a moderately good nucleophile in aprotic solvents. In this respect it is similar to the chloride, which is a poor nucleophile in protic solvents (due to strong solvation), but a good one in aprotic solvents.

Dany - 20-8-2013 at 16:45

Thanks for the reference Nicodem,

these reference clearly shows that the acetate ion cannot undergoes an SN2 in classical condition, so special solvent/phase transfer catalyst are needed to accomplish the reaction. I think, if Myeou synthesize NBu4Br from an excess of his BuBr and ammonia the rest will be easy.

Dany.



[Edited on 21-8-2013 by Dany]

Nicodem - 21-8-2013 at 09:04

Quote: Originally posted by Dany  
these reference clearly shows that the acetate ion cannot undergoes an SN2 in classical condition, so special solvent/phase transfer catalyst are needed to accomplish the reaction.

What are you talking about? The two references I provided prove no such thing. On the contrary, they describe a reaction of acetate under two conditions typically used for SN2 substitutions: the first uses a cation solvating solvent and the second uses PTC conditions. There is absolutely nothing special about it. And what do you think "classical condition" is supposed to be? There are plenty of other examples of this reaction in the literature - if you explain what conditions you want, I'm sure I can give you a reference that suits your needs.

What I can't find though, is a meaningful reference for a reaction of NaOH with 1-bromobutane, or any other simple primary alkyl bromide, to preparatively give the alcohol (not surprisingly). The article DOI: 10.1002/recl.19360551207 is supposed to contain some information about the transformation of alkyl halides to alcohols, but I currently don't have access to the journal to check, if it is about a direct or a stepwise reaction. The article DOI:10.1135/cccc19902614 mentions the formation of n-butanol as a side product in the reaction of 1-bromobutane with the ethanolic NaOH solution (n-butyl ethyl ether being the main product). Only few non-enzymatic methods exist for a direct alkyl halide to alcohol transformation. The most general appears the method employing the reaction of alkyl bromides with HgO/HBF4(aq) as described in DOI: 10.1055/s-1983-30221. Now, that is not a normal SN2 substitution.

Dany - 21-8-2013 at 09:26

Nicodem, you don't encounter PEG everyday in an SN2 reaction. also the use PTC is not too common when doing basic organic reaction like SN2. generally, SN2 are carried out in DMF or DMSO at room temperature or with heating without additive. this what i call the classical condition. We tried to perform an SN2 in DMF or DMSO under micro-wave activation, which work well, but even this (MW activation) deviate from the classical condition because you are using an exotic way to "push" the reactant to form products.

Dany.

Nicodem - 21-8-2013 at 10:15

Quote: Originally posted by Dany  
Nicodem, you don't encounter PEG everyday in an SN2 reaction. also the use PTC is not too common when doing basic organic reaction like SN2.

I use PEG quite commonly as a solvent for SN2 reactions. So do I use Aliquat 336 or tetrabutylammonium salts wherever applicable. So do many of my coworkers. PEG is particularly advantageous for nucleophiles that come as sodium or potassium salts. That you don't encounter these conditions commonly enough, it means nothing about the reaction mechanism. The reaction conditions can dictate the mechanistic pathway, but the mechanism is not bound to some specific conditions. It can still be an SN2 substitution, regardless if the solvent is PEG, DMF, DMSO, acetone, ethanol, water, or no solvent at all.
Quote:
generally, SN2 are carried out in DMF or DMSO at room temperature or with heating without additive. this what i call the classical condition.

Then you should be satisfied with this example:
"reaction of n-butyl bromide with cesium acetate in DMF at 25° for 36 h afforded n-butyl acetate in 85% yield" (cited from DOI: 10.1080/00397918308059528)

DMSO is not necessarily a good solvent for slow SN2 reactions with reactive primary alkyl halides as it is moderately nucleophilic and can itself get irreversibly O- or S-alkylated (MeI rapidly S-alkylates it; EtBr also rapidly reacts with it; for BuBr it is probably still on the edge of applicability).
Quote:
We tried to perform an SN2 in DMF or DMSO under micro-wave activation, which work well, but even this (MW activation) deviate from the classical condition because you are using an exotic way to "push" the reactant to form products.

I might understand what you meant, but for the sake of comprehension, it should be said that it has been reliably and repeatedly demonstrated that microwaves do not "activate" or "push" the reactions. Rates of homogeneous organic reactions increase in microwave reactors purely due to thermal effects (temperature profile, autoclave conditions, erroneous temperature readings, etc., but nothing that could not be equally achieved by other heating means; see DOI: 10.1002/anie.201204103). With heterogeneous mixtures there can be a specific thermal effect on the reaction rate due to mass transport effects arising from the temperature gradients that build up due to different MW energy absorption abilities of each phase. But in no case does MW heating increase the reaction rate constant. I'm aware only of one very recent study that has at least minimally convincing evidence of a MW related "activation", and even that one was on one specific sigmatropic rearrangement only (DOI: 10.1039/C3CC44610G).

Dany - 21-8-2013 at 11:53

Yes, you are using PEG and PTC in your SN2 reaction but this doesn't mean it is common everywhere. I'm talking in a general sense, and you are trying to search specific example for reaction that work only under these condition (like the cesium acetate case). You cannot generalize a condition if it work on 3 or 4 substrate.Yes we can find specific condition or reagent that work for a specific example but in general the acetate ion remain a bad choice for an SN2 reaction. Our experience with reaction done under micro-wave irradiation reveal that for certain reaction (e.g, glycosylation of mono and disaccharide) the effect is not entirely thermal. For these substrate, we found that reactions performed under MW condition are faster and "cleaner" (in term of secondary products) than the same reaction performed with normal heating which mean that micro-wave irradiation may favors certain reaction pathways over other one. What i meant by "push" is that the reaction are greatly accelerated because micro-wave irradiation decrease the activation energy of the reaction. In page 17 of the book Microwave Assisted Organic Synthesis for Jason P. Tierney, Pelle Lidström you will find:
"The calculation of the activation energy for diffusion, using Arrhenius plots of the logarithm of diffusion coefficient versus temperature under microwave and conventional thermal conditions, show a significant reduction in the activation energy under microwave conditions." which mean that microwave irradiation has a catalyst-like effect (in term of decreasing the activation energy).

Dany.

Nicodem - 26-8-2013 at 05:59

Quote: Originally posted by Dany  
I'm talking in a general sense, and you are trying to search specific example for reaction that work only under these condition (like the cesium acetate case). You cannot generalize a condition if it work on 3 or 4 substrate.Yes we can find specific condition or reagent that work for a specific example but in general the acetate ion remain a bad choice for an SN2 reaction.

There are thousands of SN2 substitutions of alkyl bromides in the literature, using all kind of acetate salts and all kinds of solvents, generally with good to excellent yields under mild conditions, and you are still trying to convince us that the acetate ion is "a bad choice"? You even go as far as lying that it only works on 3 or 4 substrates? If you truly believe it such a bad choice, then how come you are unable to find any reference to a better alternative for the transformation of alkyl bromides to alcohols?

For your information, the Mayr's nucleophilicity parameter of the acetate ion in acetonitrile is 16.90 (it is 12.71 in 90:10 acetone/water as solvation dramatically decreases its nucleophilicity - as I already explained). That is in the nucleophilicity range of aliphatic amines!
Surprisingly enough, the same parameter for the hydroxide in water is only 10.47 (hydroxide is extremely well solvated in water and hence not such a good nucleophile as one might expect). Doubtlessly, it would be much stronger nucleophile in aprotic solvents, but then alkali hydroxides are not significantly soluble in these. And even if the alkali hydroxides were soluble in aprotic solvents, it would be useless for the reaction with alkyl bromides as elimination would be the major pathway (unsolvated hydroxide is an very strong base).
Quote:
Our experience with reaction done under micro-wave irradiation reveal that for certain reaction (e.g, glycosylation of mono and disaccharide) the effect is not entirely thermal.

Based on what evidence?
Quote:
For these substrate, we found that reactions performed under MW condition are faster and "cleaner" (in term of secondary products) than the same reaction performed with normal heating which mean that micro-wave irradiation may favors certain reaction pathways over other one.

That is no evidence for non-thermal effects.
Quote:
What i meant by "push" is that the reaction are greatly accelerated because micro-wave irradiation decrease the activation energy of the reaction.

Beware that you are entering the pseudoscience discourse. Compare the activation energy of any reaction to the photon energy used in the 2.45 GHz microwave reactor and then consider how solid your evidence should be to claim what you claim (see DOI: 10.1002/anie.200400655 for an explanation).
Quote:
In page 17 of the book Microwave Assisted Organic Synthesis for Jason P. Tierney, Pelle Lidström you will find:"The calculation of the activation energy for diffusion, using Arrhenius plots of the logarithm of diffusion coefficient versus temperature under microwave and conventional thermal conditions, show a significant reduction in the activation energy under microwave conditions." which mean that microwave irradiation has a catalyst-like effect (in term of decreasing the activation energy).

It is pointless to cite a claim that has since been debunked by a more precise and better designed experimental work (see the reference I already gave you in the previous post). In short, if you really had evidence for what you claim, then why didn't you publish it? You would have earned an article in ChemCom, Angewandte or JACS as a minimum, yet you tell about it on an internet forum.

watson.fawkes - 26-8-2013 at 07:02

Quote: Originally posted by Nicodem  
Rates of homogeneous organic reactions increase in microwave reactors purely due to thermal effects (temperature profile, autoclave conditions, erroneous temperature readings, etc., but nothing that could not be equally achieved by other heating means; see DOI: 10.1002/anie.201204103).
That article is behind a paywall, and I haven't read it yet. But I have what I think should be a simple question, though it may not be. Is the driving microwave radiation used in the results in question all at the easily-available frequency band at 2.4 GHz? I ask because if there's any microwave-specific effect possible, I can't imagine it's not frequency-specific to the reagents.

Nicodem - 26-8-2013 at 12:49

Quote: Originally posted by watson.fawkes  
That article is behind a paywall, and I haven't read it yet. But I have what I think should be a simple question, though it may not be. Is the driving microwave radiation used in the results in question all at the easily-available frequency band at 2.4 GHz? I ask because if there's any microwave-specific effect possible, I can't imagine it's not frequency-specific to the reagents.

That would be one proper way to evaluate microwave effects (and potentially discern between microwave specific effects and nonthermal microwave effects), but as far as I know, all the commercial MW reactors still only operate at 2.45 GHz (I only ever worked with CEM Discovery and Biotage reactors, I never really checked the technical data of newer models).
Kappe said on one of his lectures that he would like to try other frequencies, but was put off by the obstacles. Experimenting with any magnetron that can irradiate other frequencies is strictly forbidden by some laws (international radio-diffusion laws, probably). That is, unless one obtains a licence. To obtain this, one needs to have the equipment in a proper Faraday cage and prove this is able to totally block the escaping MW. Obviously, you also need to build a custom made reactor, which is quite an expense. The answer was, that nobody yet tried and published it up to then (this was about 5 years ago).

Citation from DOI: 10.1002/anie.201204103:
Quote:
It is perhaps worth mentioning that the debate on microwave effects in organic chemistry is not new, and was already the subject of debate in Angewandte Chemie ten years ago.[32] Even at that time, the existence of nonthermal microwave effects was essentially refuted. From our perspective, after more than a decade of intense research in this area, we must now conclude that nonthermal microwave effects simply do not exist. Undoubtedly, there will be many more claims to the existence of these effects in organic chemistry (and in other fields) in the future. Unless those claims are independently verified, we would caution the scientific community against taking the existence of those effects for granted. We sincerely hope that this Essay will help the scientific community to accept the fact that microwave chemistry is not “voodoo science”,[33] but in essence an incredibly effective, safe, rapid, and highly reproducible way to perform an autoclave experiment under strictly controlled processing conditions.[34, 35]



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watson.fawkes - 26-8-2013 at 18:26

Quote: Originally posted by Nicodem  
as far as I know, all the commercial MW reactors still only operate at 2.45 GHz
[...]
Kappe said on one of his lectures that he would like to try other frequencies, but was put off by the obstacles.
I'm not too surprised. Those magnetrons and power supplies are readily available and inexpensive. As for the obstacles, the main obstacles with regulation are with the sellers, who would need certification that their emissions are acceptably low levels. Building one a tunable, high-power microwave or millimeter wave source is really a physics project (much less the reactor-specific parts), so it's there's an outsourcing issue one way or the other.

For those interested in building these, I noted this footnote 30 from DOI: 10.1002/anie.201204103:
Quote:
For an overview of commercially available microwave reactors,
see: C. O. Kappe, A. Stadler, D. Dallinger, Microwaves in
Organic and Medicinal Chemistry, 2nd ed., Wiley-VCH, Wein-
heim, 2012, Chap. 3, pp. 41–81.