Hydrolysing of Nitriles

What is Hydrolysing?

Hydrolysis usually means the rupture of chemical bonds by the addition of water. Generally, hydrolysis is a step in the degradation of a substance. In terms of the word's derivation, hydrolysis comes from Greek roots hydro "water" + lysis "separation"

Usually hydrolysis is a chemical process in which a molecule of water molecule adds to a substance. Sometimes this addition causes the substance to split into two parts. In such reactions, one fragment of the target molecule (or parent molecule) gains a hydrogen ion (H⁺) from the split water molecule. The other portion of the target molecule collects the hydroxyl group (OH⁻) of the split water molecule. In effect an acid and a base are formed (http://en.wikipedia.org/wiki/Hydrolysis)

What is Hydrolysing Nitriles?

The hydrolysis of nitriles
Introduction

When nitriles are hydrolysed you can think of them reacting with water in two stages - first to produce an amide, and then the ammonium salt of a carboxylic acid.

For example, ethanenitrile would end up as ammonium ethanoate going via ethanamide.

In practice, the reaction between nitriles and water would be so slow as to be completely negligible. The nitrile is instead heated with either a dilute acid such as dilute hydrochloric acid, or with an alkali such as sodium hydroxide solution.

The end result is similar in all the cases, but the exact nature of the final product varies depending on the conditions you use for the reaction.

Acidic hydrolysis of nitriles

The nitrile is heated under reflux with dilute hydrochloric acid. Instead of getting an ammonium salt as you would do if the reaction only involved water, you produce the free carboxylic acid.

For example, with ethanenitrile and hydrochloric acid you would get ethanoic acid and ammonium chloride.

Why is the free acid formed rather than the ammonium salt? The ethanoate ions in the ammonium ethanoate react with hydrogen ions from the hydrochloric acid to produce ethanoic acid. Ethanoic acid is only a weak acid and so once it has got the hydrogen ion, it tends to hang on to it.

Alkaline hydrolysis of nitriles
The nitrile is heated under reflux with sodium hydroxide solution. This time, instead of getting an ammonium salt as you would do if the reaction only involved water, you get the sodium salt. Ammonia gas is given off as well.
For example, with ethanenitrile and sodium hydroxide solution you would get sodium ethanoate and ammonia.

The ammonia is formed from reaction between ammonium ions and hydroxide ions.
If you wanted the free carboxylic acid in this case, you would have to acidify the final solution with a strong acid such as dilute hydrochloric acid or dilute sulphuric acid. The ethanoate ion in the sodium ethanoate will react with hydrogen ions as mentioned above.

Hydrolysis of nitriles with aqueous acid to give carboxylic acids

Description: Addition of water and acid to a nitrile leads to formation of a carboxylic acid.

Notes:

• This reaction is referred to as “acidic hydrolysis”.
• The reaction is generally used with water as solvent, so an excess of water is present. The acid used is often written as “H3O(+)”

Examples:

Notes: Note that example 4 is a cyanohydrin, so this produces an “alpha hydroxy carboxylic acid”
Mechanism:
Protonation of the nitrile nitrogen by acid (Step 1, arrows A and B) makes the nitrile carbon a better electrophile. Attack at the carbon by water (Step 2, arrows C and D) followed by proton transfer (Step 3, arrows E and F) gives a species that is in resonance with a protonated amide (arrows G and H). Addition of water to the protonated amide (Step 4, arrows I and J) followed by proton transfer (Step 5, arrows K and L) result in formation of NH3(+) which is an excellent leaving group. Expulsion of NH3 through 1,2-addition (Step 6, arrows M and N) followed by deprotonation (Step 7, arrows O and P) give the carboxylic acid.

 

Hydrolysing Nitriles In Basic Condition

The cyano group has an electropositive carbon atom due to the higher electronegativity of the nitrogen atom. The resonance dipole of the cyano group also contributes to the electropositive character of the carbon atom.

 The imine anion is a strong base and will easily pull a hydrogen atom from a water molecule in the solution.

 The imine product will undergo tautomerization to form an amide. This is favored by the bond energies of the reactant versus the product.
The amide carbonyl is electropositive and will be attacked by hydroxide anion. Use a double barbed arrow to show the movement of the electron pair from the hydroxide anion to the carbonyl carbon atom. Show another double barbed arrow to indicate the movement of the p electrons to the oxygen atom.

 The product of this reaction can reform the carbonyl and eliminate either a hydroxide anion or an amide anion. If the hydroxide ion is the leaving group, the amide is reformed. The amide anion is a much stronger base and is a very poor leaving group making this equilibrium unfavorable. A small amount can leave and this leads to the next step of the mechanism.

 

 

 My problem:

I still confused about Hydrolysing Nitriles in basic Condition why easily pull a hydrogen atom from a water molecule in the solution.?

Preparation of Nitriles

What is Nitriles?

A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, including methyl cyanoacrylate, used in super glue, and nitrile butadiene rubber, a nitrile-containing polymer used in latex-free laboratory and medical gloves. Organic compounds containing multiple nitrile groups are known as cyanocarbons.

Inorganic compounds containing the -C≡N group are not called nitriles, but cyanides instead. Though both nitriles and cyanides can be derived from cyanide salts, most nitriles are not nearly as toxic.

How to make Nitriles?

MAKING NITRILES

This page looks at various ways of making nitriles - from halogenoalkanes (haloalkanes or alkyl halides), from amides, and from aldehydes and ketones. It pulls together information from pages dealing with each of these kinds of compounds

Making nitriles from halogenoalkanes

The halogenoalkane is heated under reflux with a solution of sodium or potassium cyanide in ethanol. The halogen is replaced by a -CN group and a nitrile is produced. Heating under reflux means heating with a condenser placed vertically in the flask to prevent loss of volatile substances from the mixture.

The solvent is important. If water is present you tend to get substitution by -OH instead of -CN.

---

Note:  A solution of potassium cyanide in water is quite alkaline, and contains significant amounts of hydroxide ions. These react with the halogenoalkane. This reaction is discussed on the page about the reactions between halogenoalkanes and hydroxide ions.

Use the BACK button on your browser to return to this page if you choose to follow this link.

---

For example, using 1-bromopropane as a typical halogenoalkane:

You could write the full equation rather than the ionic one, but it slightly obscures what's going on:

The bromine (or other halogen) in the halogenoalkane is simply replaced by a -CN group - hence a substitution reaction. In this example, butanenitrile is formed.

---

Note:  If you want the mechanisms for these reactions (which differ depending on exactly what sort of halogenoalkane you are talking about), you can find them by following this link.

Use the BACK button on your browser to return to this page if you choose to follow this link.

---

Making a nitrile by this method is a useful way of increasing the length of a carbon chain. Having made the nitrile, the -CN group can easily be modified to make other things - as you will find if you explore the nitriles menu (link a the bottom of the page).

Making nitriles from amides

Nitriles can be made by dehydrating 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, you will get ethanenitrile by dehydrating ethanamide.

---

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.

---

Making nitriles from aldehydes and ketones

Aldehydes and ketones undergo an addition reaction with hydrogen cyanide. The hydrogen cyanide adds across the carbon-oxygen double bond in the aldehyde or ketone to produce a hydroxynitrile. Hydroxynitriles used to be known as cyanohydrins.

For example, with ethanal (an aldehyde) you get 2-hydroxypropanenitrile:

With propanone (a ketone) you get 2-hydroxy-2-methylpropanenitrile:

In every example of this kind, the -OH group will be on the number 2 carbon atom - the one next to the -CN group.

The reaction isn't normally done using hydrogen cyanide itself, because this is an extremely poisonous gas. Instead, the aldehyde or ketone is mixed with a solution of sodium or potassium cyanide in water to which a little sulphuric acid has been added. The pH of the solution is adjusted to about 4 - 5, because this gives the fastest reaction. The reaction happens at room temperature.

The solution will contain hydrogen cyanide (from the reaction between the sodium or potassium cyanide and the sulphuric acid), but still contains some free cyanide ions. This is important for the mechanism.

---

Note:  If you want the mechanism for this reaction, you will find it explained if you follow this link.

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

---

These are useful reactions because they not only increase the number of carbon atoms in a chain, but also introduce another reactive group as well as the -CN group. The -OH group behaves just like the -OH group in any alcohol with a similar structure.

For example, starting from a hydroxynitrile made from an aldehyde, you can quite easily produce relatively complicated molecules like 2-amino acids - the amino acids which are used to construct proteins.

---

Note:  The first step is the replacement of -OH in an alcohol by chlorine.

The second step is the reaction between a halogenoalkane and ammonia.

The final step is hydrolysis of a nitrile.

Use the BACK button on your browser to return to this page if you follow any of these links.

LACTAM

In chemistry, a lactam is a cyclic amide. The name is derived from two chemical terms, lactone, referring to a cyclic ketone, and amide, a compound containing a nitrogen atom next to a carbonyl group. Lactams are named according to the size of the cyclic ring in the lactam: -lactams, -lactams, -lactams and -lactams contain rings made of three, four, five or six atoms, respectively. -lactams are also called aziridinones. Many widely used antibiotic drugs, including the penicillins and cephalosporins, owe their activity to the presence of a -lactam structure. The lactams may have substitutions added to the nitrogen atom or any of the non-carbonyl carbon atoms in the base structure.

Synthesis

General synthetic methods exist for the organic synthesis of lactams.

• Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.
• Lactams form from cyclic ketones and hydrazoic acid in the Schmidt reaction.
• Lactams form from cyclisation of amino acids.
• Lactams form from intramolecular attack of linear acyl derivatives from the nucleophilic abstraction reaction.
• In iodolactamization  an iminium ion reacts with an halonium ion formed in situ by reaction of an alkene with iodine.

•  L actams form by copper catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction

•  Diels-Alder reaction between cyclopentadiene and chlorosulfonyl isocyanate (CSI) can be utilized to obtain both β- as well as γ-lactam. At lower temp (−78 °C) β-lactam is the preferred product. At optimum temperatures, a highly useful γ-lactam known as Vince Lactam is obtained

Beckmann Rearrangement

An acid-induced rearrangement of oximes to give amides.

This reaction is related to the Hofmann and Schmidt Reactions and the Curtius Rearrangement, in that an electropositive nitrogen is formed that initiates an alkyl migration.

---

Mechanism of the Beckmann Rearrangement

Oximes generally have a high barrier to inversion, and accordingly this reaction is envisioned to proceed by protonation of the oxime hydroxyl, followed by migration of the alkyl substituent "trans" to nitrogen. The N-O bond is simultaneously cleaved with the expulsion of water, so that formation of a free nitrene is avoided.

Schmidt Reaction

Mechanism of the Schmidt Reaction

Reaction of carboxylic acids gives acyl azides, which rearrange to isocyanates, and these may be hydrolyzed to carbamic acid or solvolysed to carbamates. Decarboxylation leads to amines.

The reaction with a ketone gives an azidohydrin intermediate, which rearranges to form an amide:

Alkenes are able to undergo addition of HN₃ as with any HX reagent, and the resulting alkyl azide can rearrange to form an imine:

Tertiary alcohols give substitution by azide via a carbenium ion, and the resulting alkyl azide can rearrange to form an imine.

Kinugasa reaction

General structure of a nitrone

A nitrone is the N-oxide of an imine and a functional group in organic chemistry. The general structure is R₁R₂C=NR₃⁺O^- where R₃ is different from H.

A nitrone is 1,3-dipole in 1,3-dipolar cycloadditions. It reacts with alkenes to form an isoxazolidine:

One example of this reaction type is the reaction of various Baylis-Hillman adducts with C-Phenyl-N-methylnitrone forming an isoxazolidine in which R₁ is phenyl, R₂ is hydrogen and R₃ is a methyl group .

Nitrones react with terminal alkynes and a copper salt to beta-lactam. This reaction is also called The Kinugasa reaction  for example in this reaction:

The first step in this reaction is a dipolar cycloaddition of the nitrone with the in situ generated copper(I) acetylide to a 5-membered ring structure which rearranges in the second step.

My Problem

Why is the β-lactams are more reactive to hydrolysis conditions than are linear amides or larger lactams?

This strain is further increased by fusion to a second ring, as found in most β-lactam antibiotics. This trend is due to the amide character of the β-lactam being reduced by the aplanarity of the system. The nitrogen atom of an ideal amide is sp²-hybridized due to resonance, and sp²-hybridized atoms have trigonal planar bond geometry. As a pyramidal bond geometry is forced upon the nitrogen atom by the ring strain, the resonance of the amid bond is reduced, and the carbonyl becomes more ketone-like. Nobel laureate Woodward described a parameter h as a measure of the height of the trigonal pyramid defined by the nitrogen (as the apex) and its three adjacent atoms. h corresponds to the strength of the β-lactam bond with lower numbers (more planar; more like ideal amides) being stronger and less reactive. Monobactams have h values between 0.05 and 0.10 angstroms (Å). Cephems have h values in of 0.20–0.25 Å. Penams have values in the range 0.40–0.50 Å, while carbapenems and clavams have values of 0.50–0.60 Å, being the most reactive of the β-lactams toward hydrolysis.