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.

STEREOCHEMISTRY

What is Stereochemistry?

Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules.

Stereochemistry is also known as 3D chemistry because the prefix "stereo-" means "three-dimensionality".The study of stereochemical problems spans the entire range of organic, inorganic, biological, physical and supramolecular chemistries. Stereochemistry includes methods for determining and describing these relationships; the effect on the physical or biological properties these relationships impart upon the molecules in question, and the manner in which these relationships influence the reactivity of the molecules in question (dynamic stereochemistry).

Introduction

Molecules can be drawn a variety of ways on paper.

These flat drawings are actually representations of three-dimensional molecules. This three-dimensional character helps to define the properties of a molecule. Changing this three-dimensional character - even in only one place in the molecule - can drastically alter the properties and applications of the molecule.

The first step in learning about stereochemistry is mastering the terminology involved. The following pages will give terms, definitions, and structural examples on the following topics that are important in stereochemistry.

• Isomers
• Constitutional Isomers
• Stereoisomers
• Conformational Isomers
• Configurational Isomers
1. Geometric Isomers
2. Optical Isomers
• Chirality
• Achirality
• Prochirality
• Enantiomers
• Diastereomers
• Rotation of Light

·         Definitions: Isomers 

Isomers are compounds that have the same molecular formula. To determine whether two molecules are isomers, just count how many atoms of each type are in both molecules. If both molecules have the same count for all of the different atoms, the molecules will be isomers.

For example, consider the following molecules.

The structure on the left has 7 carbons, 13 hydrogens, one bromine, and one oxygen, or a molecular formula of C₇H₁₃BrO. The molecule on the right has the same number of each atom and the same molecular formula. Therefore, these two molecules are isomers

Definitions: Constitutional Isomers

Constitutional isomers are compounds that have the same molecular formula and different connectivity. To determine whether two molecules are constitutional isomers, just count the number of each atom in both molecules and see how the atoms are arranged. If both molecules have the same count for all of the different atoms, and the atoms are arranged in different ways (their connectivity is different), the molecules will be constitutional isomers.

(Recall that connectivity means how the atoms are attached to one another. For example, an ether has a connectivity of C-O-C, and an alcohol has a connectivity of C-O-H.)

For example, consider the following molecules.

In the previous section, it was determined that these compounds were constitutional isomers. Notice that, by definition, constitutional isomers cannot be stereoisomers and vice versa. (Recall that constitutional isomers must have different connectivities, while stereoisomers must have the same connectivity.) Therefore, these molecules are not stereoisomers.
There are two major types of stereoisomers, conformational isomers and configurational isomers.

Definitions: Conformational Isomers

Conformational isomers are stereoisomers that can be converted into one another by rotation around a single bond.  (Note: Conformational isomers are normally best seen using Newman Projections, so this structural representation will be used in this section of the tutorial.

For example, eclipsed, gauche, and anti butane are all conformational isomers of one another. (Recall that eclipsed means that identical groups are all directly in-line with one another, gauche means that identical groups are 60 degrees from one another, and anti means that identical groups are 180 degrees from one another.)

These molecules can be interconverted by rotating around the central carbon single bond. For example, eclipsed butane can be made into gauche butane by rotating 60 degrees and into anti butane by rotating 180 degrees. Similarly, gauche butane can be made into anti butane by rotating 120 degrees

Definitions: Configurational Isomers

Configurational isomers are stereoisomers that can cannot be converted into one another by rotation around a single bond. The two main types of configurational isomers are geometric isomers and optical isomers.

Geometric isomers are molecules that are locked into their spatial positions with respect to one another due to a double bond or a ring structure.

For example, consider the following two molecules.

In the ring on the left, the methyl groups are on the same side of the ring (cis), and in the molecule on the right, the methyl groups are on opposite sides of the ring (trans). These are geometric isomers because the ring structure will not allow these molecules to interconvert

Optical isomers are molecules that differ three-dimensionally by the placement of substituents around one or more atoms in a molecule. Optical isomers were given their name because they were first able to be distinguished by how they rotated plane-polarized light. These molecules are not necessarily locked into their positions, but cannot be converted into one another, even by a rotation around a single bond.

For example, consider the following two molecules.

In the molecule on the left, the chlorine is oriented upward, and in the molecule on the right, the chlorine is oriented downward. (These molecules are presented in Wedge-Dash Notation, which will be covered in more detail in a later section in the tutorial. To learn about this notation now, click here. To navigate back to this page from the Wedge-Dash information page, use the Back button in the browser, not within the tutorial.)

Definitions: Chiral

A molecule is chiral if it is not superimposable on its mirror image. Most chiral molecules can be identified by their lack of a plane of symmetry or a center of symmetry. Your hand is a chiral object, as it does not have either of these types of symmetry.

The molecule on the left has a plane of symmetry through the center carbon. This is a mirror plane; in other words, one half of the molecule is a perfect reflection of the other half of the molecule. This molecule is not chiral because of its mirror plane.

Definitions: Achiral

A molecule is achiral if it is superimposable on its mirror image. Most achiral molecules do have a plane of symmetry or a center of symmetry. Achiral molecules that contain a stereocenter are called meso.

The molecules discussed in the previous section are achiral because they possess either a plane of symmetry or a center of symmetry.

Definitions: Prochiral

A molecule is prochiral if the addition of a new group or an exchange of one group on the molecule would create a new stereocenter and, therefore, a chiral molecule. A prochiral atom must be bonded to three different groups before any change is made.

For example, consider the following molecules.

The molecule on the left is prochiral because a new stereocenter can be made by replacing one group on the carbon marked with an asterisk (*) with a new one. The molecule on the right is prochiral because a new stereocenter can be made by adding a new group to the carbon marked with an asterisk.

Definitions: Enantiomers

Now that chirality within a molecule has been discussed, the relationships between two or more chiral molecules can be determined.

Enantiomers are chiral molecules that are mirror images of one another. Furthermore, the molecules are non-superimposable on one another. This means that the molecules cannot be placed on top of one another and give the same molecule. Chiral molecules with one or more stereocenters can be enantiomers. It is sometimes difficult to determine whether or not two molecules are enantiomers. For introductory purposes, simple molecules will be used as examples. More complex examples will be given later.

For example, consider the following molecules.

These molecules are mirror images of one another. Additionally, these molecules are non-superimposable because if one of these molecules, the one on the right, is flipped 180 degrees (so that the chlorines are aligned, as shown below), the stereochemistry is different (one chlorine is wedged and the other is dashed). Therefore, these molecules are enantiomers. (Note: When flipping molecules using the Wedge-Dash notation, groups that are wedged become dashed, and groups that are dashed become wedged.)

Definitions: Diastereomers

Diastereomers are stereoisomers that are not mirror images of one another and are non-superimposable on one another. Stereoisomers with two or more stereocenters can be diastereomers. It is sometimes difficult to determine whether or not two molecules are diastereomers. For introductory purposes, simple molecules will be used as examples. More complex examples will be given later.

For example, consider the following molecules.

These molecules are not mirror images of one another. Additionally, these molecules are non-superimposable because if one of these molecules is flipped 180 degrees (so that the alcohols and methyls are aligned, as shown below), the stereochemistry is different at one carbon (the alcohols) and the same at another carbon (the methyls). Therefore, these molecules are diastereomers.

Definitions: Rotation of Light

Optical isomers are named because they can rotate a plane of polarized light. Light is plane-polarized if all of the light waves are vibrating in the same, parallel, direction. This is shown below with a single wave (line) below.

If plane-polarized light is rotated 45 degrees to the left (counterclockwise), this is known as levorotatory (l, -); this is shown below in the image on the left. If plane-polarized light is rotated 45 degrees to the right (clockwise) this is known as dextrorotatory (d, +); this is shown below in the image on the right. Both d and l rotations are considered by looking in the direction the light is traveling; in other words, the light is moving away from you, not toward you.

Three-Dimensional Representations: Cyclic Structures

Cyclic, or ring, structures can also be drawn in a variety of ways. Rings can have many different sizes, with the smallest ring being cyclopropane (three carbons). The most common ring types in organic chemistry are cyclopentane (five carbons) and cyclohexane (six carbons). Cyclohexane will be discussed in this tutorial, and its three main structural types can be seen above. From left to right, these structures are the Wedge-Dash Notation, the Haworth Projection, and the Chair Conformation.

Three-Dimensional Representations: Straight-Chain Structures

There are four main types of representations for straight-chain molecules, as shown above. From left to right, these structures are the Sawhorse Projection, the Fisher Projection, the Newman Projection, and the Wedge-Dash notation.

http://www.chemeddl.org/resources/stereochem/introduction1.htm