Acetylides from Alkynes, And Substitution Reactions of Acetylides

Alkylation of acetylides

• Terminal alkynes have unusually acidic C–H bonds (pK_a 25). Treatment with a strong base such as sodium amide (NaNH₂) gives an acetylide, the name for the conjugate base of a terminal alkyne.
• Acetylides are more stable than the conjugate bases of alkenes and alkanes due to the fact that the lone pair is held in an sp-hybridized orbital which has 50% s-character. Since s-orbitals are held closer to the positively charged nucleus than p-orbitals, the electrons in this orbital are more stable (i.e. have less potential energy)
• Acetylides are strong bases, but can also act as nucleophiles in nucleophilic substitution reactions (S_N2) with alkyl halides to form substituted acetylenes.
• These reactions work best for primary and methyl alkyl halides.
• Attempts to form C-C bonds via S_N2 reactions with secondary alkyl halides almost always results in elimination (E2) instead, due to the high basicity of the acetylide ion.
• The reaction of acetylides with alkyl halides one of the most important reactions you will learn in first semester organic chemistry because it provides a versatile way of forming C-C bonds and extending the carbon chain.
• This reaction is therefore a key entry point in planning the synthesis of various molecules, especially since the resulting alkynes can be hydrogenated to alkanes (and partially hydrogenated to alkenes, as we’ll soon see). [See article – Partial Hydrogenation of Alkynes to cis-Alkenes With Lindlar’s Catalyst]

Table of Contents

1. 1. Terminal Alkynes Are Acidic!
   2. Alkylations of Acetylides With Primary Alkyl Halides: Finally, Some Carbon-Carbon Bond Formation!
   3. Alkylation of Acetylides – Some Practice Questions
   4. Synthesis of Substituted Acetylenes – Practice Questions
   5. Other Reactions of Acetylides – Epoxide Opening and Addition to Aldehydes/Ketones
   6. Summary
   7. Notes
   8. Quiz Yourself!
   9. (Advanced) References and Further Reading

1. Terminal Alkynes Are Acidic!

Among hydrocarbons, terminal alkynes have a very special property.  Their C-H bonds are unusually acidic (pK_a 25).

The alkyne C-H bond is sp-hybridized. When C-H is deprotonated, the resulting carbanion is held in an orbital with 50% s-character. Since s-orbitals are closer to the nucleus than p-orbitals,  this means that the electrons experience greater stabilization from the positively charged nucleus than the conjugate bases of alkenes and alkanes.

Any factor which stabilizes a lone pair of electrons tends to reduce its basicity. (See article – Key Factors That Influence Acidity). In fact,  just thinking of “basicity” as a synonym for “lone-pair instability” can get you pretty far in organic chemistry! 

A common choice of base for deprotonating the C-H bond of acetylenes is sodium amide (NaNH₂), often used in its conjugate base, liquid ammonia (NH₃). NaNH₂ can also be used to deprotonate the great-granddaddy of all alkynes, acetylene itself.   [Note 1]

Note – don’t confuse NaNH₂/NH₃  [strong base!]  with sodium in ammonia,Na/NH₃  [reducing agent for triple bonds!]  [Note 2]

Acid-base reactions spontaneously proceed in the direction that gives weaker acids from stronger acids. (I lovingly call this the “Principle Of Acid-Base Mediocrity” – See article: How To Use a pKa Table).

Since we are proceeding from a stronger acid (terminal alkyne, pK_a 25) towards a weaker conjugate acid (NH₃, pK_a 38) the acid-base equilibrium here will be favorable.

On the other hand, the acid-base reaction between NaNH₂ and alkenes (pK_a 42) or alkanes (pK_a 50) is unfavorable since it would result in a stronger acid (NH₃, pK_a 38), as well as a stronger base. Remember – the stronger the acid, the weaker the conjugate base! 

2. S_N2 Reactions of Acetylides With Alkyl Halides: Finally, Some Carbon-Carbon Bond Formation!

OK. So we can make acetylides. Now what?

Well, acetylides are excellent nucleophiles.  They react with alkyl halides to give internal alkynes, in a reaction known as nucleophilic (aliphatic) substitution.

It is a substitution reaction because a new bond is formed (C-C) at the same carbon where a bond is broken (C-X, where X is a good leaving group). ( See article: What Makes a Good Leaving Group?).

More specifically, the substitution proceeds through an S_N2 mechanism (substitution, nucleophilic, bimolecular rate-determining step) since the C–C bond is being formed at the same time that the C–X bond breaks. The reaction occurs via donation of the nucleophile lone pair into the sigma* orbital of the C-X bond, often referred to as a “backside attack”. It results in inversion of configuration at the carbon, although inversion can only be observed with carbons bearing a chiral center. (See article: The S_N2 Mechanism)

The reaction works best for primary (and methyl) alkyl halides due to their lack of steric hindrance.

Secondary alkyl halides tend to give elimination (E2) instead of substitution, since there is more steric hindrance at a secondary carbon and acetylide is still a very strong base – even if it’s a weak base for a hydrocarbon!

All right. Perhaps you’ve already covered nucleophilic substitution reactions, and this reaction might not seem like such a big deal to you. Fair.

I would like to draw your attention, however, to the key bond that is formed in this reaction: C–C.

Up until this point, it’s unlikely you’ve covered any carbon-carbon bond forming reactions. If you’ve covered any at all, it might be the cyanide ion (e.g. NaCN) with alkyl halides. That isn’t so important for our purposes since we don’t cover reactions of cyano groups until later on in Org 2.

Since organic chemistry is ultimately the chemistry of carbon, having the ability to form a new C-C bond from a terminal alkyne via an S_N2 reaction is huge because it allows us to plan the synthesis of essentially any linear hydrocarbon from acetylene, provided we can partner it with primary alkyl halide.

(Those primary alkyl halides can themselves be made from various reactions with acetylene, a point we’ll get to later in this chapter!). 

The example below, for instance, shows the synthesis of 5-decyne:

This reaction is extremely versatile. Simply by changing the identity of the alkyl halide, we can  tack on pretty much any alkyl group we want –  so long as it’s primary – which gives us access to a huge variety of linear hydrocarbons!

3. Alkylation of Acetylides – Some Practice Questions

We’ll get to some synthesis applications a little further below. In the meantime, see if you can draw the product of this reaction:

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Here is another example of a reaction between an acetylide and an alkyl halide. Can you draw the product? (D is deuterium, the heavy isotope of hydrogen).

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Draw the product of the reaction below:

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In the reaction below, the acetylide is treated with an alkyl halide containing two leaving groups. Draw the product!

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4. Practice Questions – Synthesis of Acetylenes

As mentioned above in section two, the S_N2 reaction between acetylides and alkyl halides means that we can build up pretty much any linear alkyne from acetylene, provided that we have the necessary (linear) alkyl halides.

The questions below ask you to show how you would synthesize internal alkynes from acetylene and alkyl halides.

Here’s one synthesis problem:

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A second, slightly more difficult synthesis question.

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More of the same thing!

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5. Reaction of Acetylides With Other Nucleophiles

Acetylides don’t just react with alkyl halides! They are versatile nucleophiles with other electrophiles as well, although you might not see some of these reactions until later in your course, or perhaps in the second semester of a two-semester course.

Epoxides are 3-membered cyclic ethers with considerable ring strain (about 13 kcal/mol) (See article – Epoxides, The Outlier of the Ether Family).  Acetylides will react with epoxides at the least substituted position to form new C-C bonds (See Article: Epoxide Ring-Opening With Base)

Acetylides will also add to aldehydes and ketones through nucleophilic addition to the C-O pi bond. In this respect the reaction of acetylides is essentially identical to those of Grignard reagents.

6. Summary

• Acetylides react with primary and methyl alkyl halides to give new C-C bonds via nucleophilic substitution (S_N2 mechanism).
• They tend to give elimination with secondary alkyl halides.
• This is an extremely important reaction for first semester organic chemistry, as it allows for formation of longer carbon chains from acetylene.

In the next article in this series, we will show how the triple bond of alkynes can be partially hydrogenated to give alkenes. (See article: Partial Hydrogenation of Alkynes to Give Alkenes)

Notes

Note 1. Conditions for the deprotonation of acetylene are here. Note that acetylene is a gas, so it has to be bubbled through a solution containing NaNH₂ in ammonia. These days, it’s more common just to just purchase the conjugate base of acetylene (such as lithium acetylide, diethylamine complex) directly from a commercial supplier like Aldrich and weigh it out.

Note 2. By no means is NaNH₂ the only base used for deprotonating acetylenes, it just seems to be the textbook reagent of choice. Grignard and organolithium reagents are also often used to form acetylides.

Quiz Yourself!

[Quizzes]

(Advanced) References and Further Reading

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. THE PREPARATION AND ALKYLATION OF METAL ACETYLIDES IN LIQUID AMMONIA*
   T. H. Vaughn, G. F. Hennion, R. R. Vogt, and J. A. Nieuwland
   The Journal of Organic Chemistry 1937 02 (1), 1-22
   DOI: 10.1021/jo01224a001
2. 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.
3. 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.
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.