Acetylides from Alkynes, And Substitution Reactions of Acetylides

Deprotonation of Alkynes And Substitution Reactions (S_N2) Of Acetylides Are The Two Most Important Reactions Of Alkynes

• If you treat a “terminal alkyne” (an alkyne that ends in a C-H bond) with a strong base such as NaNH₂, it will be deprotonated to form its conjugate base – called an “acetylide”.
• These acetylides are extremely useful for us, as they participate in S_N2 reactions with primary alkyl halides to form new carbon-carbon bonds.
• This is one of the first ways we learn to build up longer carbon chains, and therefore becomes a very important reaction to know when solving synthesis problems.

Table of Contents

1. Deprotonation of Alkynes To  Give “Acetylides”
2. Alkylation of Acetylides With Alkyl Halides
3. Why Is This So Important? Because It Forms A  New Carbon-Carbon Bond!
4. Summary: Acetylide Formation and Carbon-Carbon Bond Formation
5. (Advanced) References and Further Reading

1. Alkynes Are Unusually Acidic. Deprotonation of Alkynes Gives “Acetylides”

Let’s start with an important fact. Alkynes are unusually acidic hydrocarbons.  Recall that the acidity of a compound is related to the stability of the conjugate base. In an alkyne, where the carbon is sp hybridized, the lone pair resides in an orbital with 50% s character [the 2s orbital is closer to the positively-charged nucleus than the 2p orbital, increasing stability]. Compare that to alkenes (sp², 33% s-character) and alkanes (sp³, 25% s character) and we have an explanation as to why alkynes have a pK_a of 25, which is a factor of 10¹⁷ more acidic than your typical alkene (pK_a about 42) and 10²⁵ more acidic than alkanes (pK_a 50).

This means that alkynes can be deprotonated without resorting to heavy artillery (i.e. organolithium bases, or Schlösser’s base – not that you probably need to know about that particular reagent) required to deprotonate alkenes. Instead, readily available sodium amide (NaNH₂) the conjugate base of ammonia (pK_a 38) can be used, which is a big plus for convenience.

Deprotonation of alkynes with a strong base yields the conjugate base, often referred to as an “acetylide” :

So that’s certainly one way in which the chemistry of alkynes is distinct from that of alkenes: alkynes can be readily deprotonated.

2. Alkylation of Acetylides With Alkyl Halides via Substitution

Knowing that, care to take a guess what the next extension of this is? You might recall that in all cases that the conjugate base is a stronger nucleophile. And almost every reaction in organic chemistry involves the attack of a nucleophile upon an electrophile. So one logical application of being able to deprotonate alkynes into acetylide ions is that they are excellent nucleophiles and we can combine them with various electrophiles. 

One of the simplest and yet most powerful reactions in terms of generating a diverse array of functional groups is the S_N2 reaction, in which a nucleophile attacks a carbon with a good leaving group (alkyl halides or sulfonates). The “big barrier” to the S_N2 is steric hindrance so the reaction works particularly well for methyl and primary alkyl halides (secondary alkyl halides are a bit iffy in this context).

Here’s an example of how the S_N2 can be applied to the synthesis of internal alkynes.

It’s a typical substitution reaction: we’re forming and breaking a bond on the same carbon.

Now comes the important part. This S_N2 reaction is particularly useful.

3. Why Is This So Important? Because It Forms A  New Carbon-Carbon Bond!

Notice the type of bond that’s being formed  here: we’re forming a carb0n-carbon bond. If you’ve read previous posts leading up to this one, scratch your head for a moment: can you think of any examples where we’re forming a carbon-carbon bond? Probably not! [one example is cyanide ion with an alkyl halide].

Why is this important? Consider that organic chemistry is the study of carbon containing molecules. The reaction of acetylides with alkyl halides, therefore, is a way of extending the carbon skeleton of the molecule. We haven’t yet learned any other reactions that perform this function nearly as well. 

4. Summary: The Two Most Important Reactions of Alkynes

If you are studying alkynes, it is likely that in the near future you will be asked to solve  “synthesis” problems, where you build more complex molecules out of simpler parts. The S_N2 reaction of acetylides with alkyl halides often plays a pivotal role, since it allows for the extension of the carbon chain. So pay particular attention to it!

In the next post, we’ll talk about some other reactions that are unique to alkynes, and see – once again – how stereochemistry can rear its ugly head.

Next Post: Partial Reduction of Alkynes

Notes

(Advanced) References and Further Reading

Not much to say here. This is a pretty standard acid-base reaction, driven by the acidity of the sp-H atom. The utility lies in that this is still a robust method of C-C bond formation, and a useful way to introduce alkynyl groups if desired.

1. PREPARATION AND USE OF LITHIUM ACETYLIDE: 1-METHYL-2-ETHYNYL-endo-3,3-DIMETHYL-2-NORBORNANOL
   Mark Midland, Jim I. McLoughlin, and Ralph T. Werley Jr
   Org. Synth. 1990, 68, 14
   DOI: 10.15227/orgsyn.068.0014
   I was initially a little surprised that something like this was published so recently in Organic Syntheses, but reading the discussion gives some context. The selective formation of the monolithiated species from deprotonation of acetylene is tricky.
2. 1-PHENYL-1-PENTEN-4-YN-3-OL
   Lars Skattebøl, E. R. H. Jones, and Mark C. Whiting
   Org. Synth. 1959, 39, 56
   DOI: 10.15227/orgsyn.039.0056
   Alkynyl Grignards can also be formed by deprotonation of a terminal alkyne with a Grignard reagent, as this procedure demonstrates.
3. Stable Carbonium Ions. XVIII.1a Alkynyl Carbonium Ions
   Charles U. Pittman Jr. and George A. Olah
   Journal of the American Chemical Society 1965, 87 (24), 5632-5637
   DOI: 10.1021/ja00952a021
   The experimental procedure has many methods for forming nucleophilic alkynyl groups, which are then reacted with various ketones to form alkynyl alcohols, and then ionized in superacid media in order to characterize the resulting carbocations.
4. n-BUTYLACETYLENE
   Kenneth N. Campbell and Barbara K. Campbell
   Org. Synth. 1950 30, 15
   DOI: 10.15227/orgsyn.030.0015
   An extremely simple example of this reaction. The deprotonation is done with Na metal in liquid ammonia, and care has to be taken to avoid the conditions of dissolving metal reduction (the procedure states that the reaction should not turn blue)
5. Synthesis of Unsymmetrical Alkynes via the Alkylation of Sodium Acetylides. An Introduction to Synthetic Design for Organic Chemistry Students
   Jennifer N. Shepherd and Jason R. Stenzel
   Journal of Chemical Education 2006, 83 (3), 425
   DOI: 10.1021/ed083p425
   A nice paper that describes the adaptation of this reaction for undergraduate teaching labs.