Dehydration of Amides

Dehydration of amides to give nitriles

Description: Primary amides can be converted to nitriles with a dehydrating reagent such as P2O5 .

Notes: Note that the net effect of this reaction is to remove two H atoms and one O from the amide. For this reason this is called a “dehydration”.

Only primary amides work for this reaction. Other reagents can be used for this, however, such as thionyl chloride (SOCl2)

Examples:

Notes:

Mechanism:

The reaction begins with the oxygen of the amide attacking phosphorus (through a resonance form) forming an O–P bond (Step 1, arrows A, B, and C). After a proton transfer (Step 2, arrows D and E) a lone pair from nitrogen forms a new C–N bond, expelling oxygen (Step 3, arrows F and G). Finally the nitrogen is deprotonated (Step 4, arrows H and I) to give the neutral nitrile.

Notes:

There are certainly other reasonable ways to draw proton transfer (Step 2) as well as other bases to use for deprotonation (Step 4) besides phosphate. This is just one reasonable possibility.

It’s also reasonable to show fragmentation of the P–O–P bond in step 3, although for simplicity’s sake this was not drawn.

What is Phosphorus pentoxide (P₂O₅)?

Phosphorus pentoxide is a chemical compound with molecular formula P₄O₁₀ (with its common name derived from its empirical formula, P₂O₅). This white crystalline solid is the anhydride of phosphoric acid. It is a powerful desiccant.

Phosphorus pentoxide is a potent dehydrating agent as indicated by the exothermic nature of its hydrolysis:

P₄O₁₀ + 6 H₂O → 4 H₃PO₄   (–177 kJ)

However, its utility for drying is limited somewhat by its tendency to form a protective viscous coating that inhibits further dehydration by unspent material. A granular form of P₄O₁₀ is used in desiccators.

Consistent with its strong desiccating power, P₄O₁₀ is used in organic synthesis for dehydration. The most important application is for the conversion of amides into nitriles.

P₄O₁₀ + RC(O)NH₂ → P₄O₉(OH)₂ + RCN

The indicated coproduct P₄O₉(OH)₂ is an idealized formula for undefined products resulting from the hydration of P₄O₁₀.

Supposedly, when combined with a carboxylic acid, the result is the corresponding anhydride

P₄O₁₀ + RCO₂H → P₄O₉(OH)₂ + [RC(O)]₂O

The "Onodera reagent", a solution of P₄O₁₀ in DMSO, is employed for the oxidation of alcohols.^[9] This reaction is reminiscent of the Swern oxidation.

The desiccating power of P₄O₁₀ is strong enough to convert many mineral acids to their anhydrides. Examples: HNO₃ is converted to N₂O₅;  H₂SO₄ is converted to SO₃;  HClO₄ is converted to Cl₂O₇.

 

Why do we use Phosphorus pentoxide when dehydration of Nitriles?

Molecular Structure of DAHA and ENTA The NSWC-IHD initiated a program in 1998 targeting the replacement of lead based primary explosive initiating compounds (lead styphnate and lead azide), Applications of phosphorus pentoxide Phosphorus pentoxide is a potent dehydrating agent as indicated by the exothermic nature of its hydrolysis:

P4O10 + 6 H2O → 4 H3PO4 (–177 kJ)

However, its utility for drying is limited somewhat by its tendency to form a protective viscous coating that inhibits further dehydration by unspent material. A granular form of P4O10 is used in desiccators. Consistent with its strong desiccating power, P4O10 is used in organic synthesis for dehydration. The most important application is for the conversion of amides into nitriles

P4O10 + RC(O)NH2 → P4O9(OH)2 + RCN

Supposedly, when combined with a carboxylic acid, the result is the corresponding anhydride

P4O10 + RCO2H → P4O9(OH)2 + [RC(O)]2O

The desiccating power of P4O10 is strong enough to convert many mineral acids to their anhydrides. Examples: HNO3 is converted to N2O5; H2SO4 is converted to SO3; HClO4 is converted to Cl2O7.

(http://www.sciencemadness.org/talk/viewthread.php?tid=19184)

The lack of base character in amides

Unusually for compounds containing the -NH₂ group, amides are neutral. This section explains why -NH₂ groups are usually basic and why amides are different.

The usual basic character of the -NH₂ group

Simple compounds containing an -NH₂ group such as ammonia, NH₃, or a primary amine like methylamine, CH₃NH₂, are weak bases. A primary amine is a compound where the -NH₂ group is attached to a hydrocarbon group.

The active lone pair of electrons on the nitrogen atom in ammonia can combine with a hydrogen ion (a proton) from some other source - in other words it acts as a base.

With a compound like methylamine, all that has happened is that one of the hydrogen atoms attached to the nitrogen has been replaced by a methyl group. It doesn't make a huge amount of difference to the lone pair and so ammonia and methylamine behave similarly.

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Note:  The reasons that these are bases and the differences between them (because there are slight differences) are explored in some detail on a page about organic bases. It would be useful to read this page before you go on because it is relevant to what is coming next.

If you follow this link, use the BACK button on your browser to return to this page.

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For example, if you dissolve these compounds in water, the nitrogen lone pair takes a hydrogen ion from a water molecule - and equilibria like these are set up:

Notice that the reactions are reversible. In both cases the positions of equilibrium lie well to the left. These compounds are weak bases because they don't hang on to the incoming hydrogen ion very well.

Both ammonia and the amines are alkaline in solution because of the presence of the hydroxide ions, and both of them turn red litmus blue.

Why doesn't something similar happen with amides?

Amides are neutral to litmus and have virtually no basic character at all - despite having the -NH₂ group. Their tendency to attract hydrogen ions is so slight that it can be ignored for most purposes.

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Note:  If you haven't already done so, follow the link mentioned above to the page about organic bases, and read the bit about phenylamine. It is directly relevant to what's next.

Use the BACK button on your browser to return to this page.

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We need to look at the bonding in the -CONH₂ group.

Like any other double bond, a carbon-oxygen double bond is made up of two different parts. One electron pair is found on the line between the two nuclei - this is known as a sigma bond. The other electron pair is found above and below the plane of the molecule in a pi bond.

A pi bond is made by sideways overlap between p orbitals on the carbon and the oxygen.

In an amide, the lone pair on the nitrogen atom ends up almost parallel to these p orbitals, and overlaps with them as they form the pi bond.

amidedeloc.gif

The result of this is that the nitrogen lone pair becomes delocalised - in other words it is no longer found located on the nitrogen atom, but the electrons from it are spread out over the whole of that part of the molecule.

This has two effects which prevent the lone pair accepting hydrogen ions and acting as a base:

• Because the lone pair is no longer located on a single atom as an intensely negative region of space, it isn't anything like as attractive for a nearby hydrogen ion.
• Delocalisation makes molecules more stable. For the nitrogen to reclaim its lone pair and join to a hydrogen ion, the delocalisation would have to be broken, and that will cost energy.

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Note:  If you want to look in more detail at the bonding in the carbon-oxygen double bond, you could follow this link.

If you do choose to follow this link, it will probably take you to several other pages before you are ready to come back here again. Use the BACK button (or HISTORY file or GO menu) on your browser to return to this page later.

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The dehydration of amides

Amides are dehydrated by heating a solid mixture of the amide and phosphorus(V) oxide, P₄O₁₀.

Water is removed from the amide group to leave a nitrile group, -CN. The liquid nitrile is collected by simple distillation.

For example, with ethanamide, you will get ethanenitrile.

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Note:  This is a just a flow scheme rather than a proper equation. I haven't been able to find a single example of the use of the full equation for this reaction. In fact the phosphorus(V) oxide reacts with the water to produce mixtures of phosphorus-containing acids.

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The Hofmann Degradation

The Hofmann degradation is a reaction between an amide and a mixture of bromine and sodium hydroxide solution. Heat is needed.

The net effect of the reaction is a loss of the -CO- part of the amide group. You get a primary amine with one less carbon atom than the original amide had.

The general case would be (as a flow scheme):

If you started with ethanamide, you would get methylamine. The full equation for the reaction is:

The Hofmann degradation is used as a way of cutting a single carbon atom out of a chain.

 

Are there another reagent that is used to dehydrate the amide?

Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH₃CO)₂O.^[1] Commonly abbreviated Ac₂O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis. It is a colorless liquid that smells strongly of acetic acid, formed by its reaction with the moisture in the air.

Formic anhydride is an even simpler acid anhydride, but it spontaneously decomposes, especially once removed from solution.