_” 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).

History and Significance

Louis Pasteur could rightly be described as the first stereochemist, having observed in 1849 that salts of tartaric acid collected from wine production vessels could rotate plane polarized light, but that salts from other sources did not. This property, the only physical property in which the two types of tartrate salts differed, is due to optical isomerism. In 1874, Jacobus Henricus van 't Hoff and Joseph Le Bel explained optical activity in terms of the tetrahedral arrangement of the atoms bound to carbon.

Cahn-Ingold-Prelog priority rules are part of a system for describing a molecule's stereochemistry. They rank the atoms around a stereocenter in a standard way, allowing the relative position of these atoms in the molecule to be described unambiguously. A Fischer projection is a simplified way to depict the stereochemistry around a stereocenter

1. What are we talking about?

        The bottom line of this whole chapter is learning the difference between isomers. There are two types of isomers, constitutional and stereoisomers. Constitutional isomers are two compounds that have the same atoms present, but differ in their connectivity. ie:

        These compounds contain the same number of atoms, but the oxygen has been moved to form an ether instead of an alcohol. Therefore, these compounds are constitutional isomers.

Stereoisomers also have the same atoms present, however the connectivity is the same. This means the same number of hydrogens will be attached to each carbon and the same number of carbons will be attached to each carbon. Picture this:

Now, these structures both appear to be the same, but careful observation will reveal that the amine groups attached are in the cis conformation on the left and the trans conformation on the right. Therefore, the same atoms are present, but just in a different spatial arrangement.

Not to beat this idea into your head, but here is another example of a stereoisomer, but this time we will use a hydrocarbon chain.

Notice that the chain on the left is in the cis conformation at the double bond and the chain on the right is trans. This makes them stereoisomers.

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2. I understand that chiral compounds are mirror images of each other that are not superposable, but how do I tell they are superposable?

          The easiest way to tell if the mirror image is superimposable or not and superposable is to find the stereochemistry at the stereocenter. This entails you to find the stereocenter first and then label the groups attached to it in order of their priority. This means the atom with the highest atomic number will be labeled A and the next highest B. The next step is to rotate the molecule so the D group is facing away from you.

ie.

If the groups go from A to C clockwise, it is in the R configuration. If the groups are arranged counterclockwise, it is in the S configuration.

Practice a few

A B C

          A has two stereocenters. The top stereocenter is an R configuration and the bottom stereocenter is an S configuration. For B the stereocenter is an S. C does not have to be considered because there are two of the same groups attached, and is not chiral.

If the two compounds you are looking at are mirror images of each other, but the configuration at the stereocenter differs, they are not superposable. Therefore they are chiral compounds. If they are superposable, then they are achiral.

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3. How do I tell the difference between an Enantiomer and Diastereomer?

       The easiest way to tell apart an enantiomer and a diastereomer is to look at whether or not the compounds are mirror images of each other. The best way to learn this is through practice. Here are a few examples, see if you can determine whether or not the compounds are enantiomers, the same, or diastereomers.

Hint: first determine if the compounds are mirror images of each other, and then find the individual stereochemistry around each chiral carbon. Remember the hand rule or the clockwise/counterclockwise arrangement discussed in the previous section.

D

        If you are having problems determining the configuration at each stereocenter, I suggest building a model.

A is a pair of diastereomers, because the configuration is S, S in the first compound and R,S in the second compound.

B is a tricky one. They are both in the trans configuration and there is a plane of symmetry. Also, notice there is no carbon with four different groups. Therefore, they are not enantiomers and there is no stereochemistry.

C does not have a carbon with four different groups, so it does not have a stereocenter either.

D is a pair of enatiomers. Notice they are mirror images of each other.

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4. There is an R and there is an S, but I don’t know what to do with them. Help!

If you have read the past few sections you know what the S and R designations are. They tell what type of stereochemistry is found at the stereocenter. Finding the stereochemistry at the stereocenters can help determine whether two compounds are enantiomers or diastereomers. Also, R and S versions of the same compound will have different optical activity values.

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5. Quick Review of optical activity

Optical activity is the only physical property that differs from one enantiomer to the next. Optical activity is measured when plane polarized light is passed through a compound. When the light passes through the compound, it is bent either with positive rotation (dextrorotary) or with negative rotation (levorotary). There is no correlation between positive or negative rotation with the S or R configuration. S can be either dextrorotary or levorotary and the R enantiomer will be the opposite of the S. The value given to optical activity is specific rotation. The equation to figure out specific rotation can be found page 203 in your textbook.

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6. Okay, I’m getting this stereocenter thing, but somebody had to go and screw everything up and stick two stereocenters together.

When dealing with two or more stereocenters on the same compound, there are a lot of possibilities. The first possibility is that the compounds are enantiomers of each other, the second that they are diastereomers, and finally that they can be meso compounds. Diastereomers occur when the compounds have the same chemical formula, but are not mirror images of each other.

ie.

Now look at these same atoms arranged differently to form an enatiomer. These compounds are mirror images of each other. However, they do have different stereochemistries, which makes them enantiomers.

You should also look at these next compounds and discover what makes them different from the above.

       These compounds appear to be enatiomers, because they are mirror images of each other. They really are not. The middle two compounds are the meso compound, since they are the same. The outside two compounds are enatiomers of each other. Therefore, a meso compound is observed with stereoisomers where you would expect four different possible structures (two pairs of enantiomers), but there are only three stereoisomers.

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7. Fischer Projections doesn’t mean a weekend out on the lake. How do I interpret them?

Fischer projections are a quick way to show three dimensions without the hassle of having to draw 3-D. They are very effective for those of us who lack artistic skills. When you look at the diagram the horizontal lines represent atoms that are coming out at you. The vertical lines mean they are going away from you. Fischer projections can be rotated 180 degrees and still be the same compound. However, if you flip it vertically or horizontally, it becomes the enantiomer.

This Fischer projection has been flipped horizontally. These two are enatiomers of each other. The first projection has an S, R configuration. The second projection has an R, S configuration.

Now lets look at a vertically flipped diagram.

T

hese compounds are enatiomers of each other.

Finally, notice what happens when the diagrams are rotated 180 degrees in the plane of the paper.

The configuration at each stereocenter remains the same.

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8. Cyclic Compounds

If you are anything like me, it is very hard for you to determine the stereochemistry in cyclic compounds the best way is just practice. Hopefully, this area will help. Do your best to determine the stereochemistry.

Analysis:

_" NITRILES Part.II "_

What are nitriles?

            Nitriles contain the -CN group, and used to be known as cyanides.

Some simple nitriles

            The smallest organic nitrile is ethanenitrile, CH₃CN, (old name: methyl cyanide or acetonitrile - and sometimes now called ethanonitrile). Hydrogen cyanide, HCN, doesn't usually count as organic, even though it contains a carbon atom.

             Notice the triple bond between the carbon and nitrogen in the -CN group.

The three simplest nitriles are:

CH3CN	ethanenitrile
CH3CH2CN	propanenitrile
CH3CH2CH2CN	butanenitrile

When you are counting the length of the carbon chain, don't forget the carbon in the -CN group. If the chain is branched, this carbon usually counts as the number 1 carbon.

Physical properties

  A. Boiling points

The small nitriles are liquids at room temperature.

nitrile	boiling point (°C)
CH3CN	82
CH3CH2CN	97
CH3CH2CH2CN	116 - 118

These boiling points are very high for the size of the molecules - similar to what you would expect if they were capable of forming hydrogen bonds.

However, they don't form hydrogen bonds - they don't have a hydrogen atom directly attached to an electronegative element.

They are just very polar molecules. The nitrogen is very electronegative and the electrons in the triple bond are very easily pulled towards the nitrogen end of the bond.

Nitriles therefore have strong permanent dipole-dipole attractions as well as van der Waals dispersion forces between their molecules.

  B. Solubility in Water

Ethanenitrile is completely soluble in water, and the solubility then falls as chain length increases.

nitrile	solubility at 20°C
CH3CN	miscible
CH3CH2CN	10 g per 100 cm3 of water
CH3CH2CH2CN	3 g per 100 cm3 of water

           The reason for the solubility is that although nitriles can't hydrogen bond with themselves, they can hydrogen bond with water molecules.

One of the slightly positive hydrogen atoms in a water molecule is attracted to the lone pair on the nitrogen atom in a nitrile and a hydrogen bond is formed.

              There will also, of course, be dispersion forces and dipole-dipole attractions between the nitrile and water molecules.

Forming these attractions releases energy. This helps to supply the energy needed to separate water molecule from water molecule and nitrile molecule from nitrile molecule before they can mix together.

As chain lengths increase, the hydrocarbon parts of the nitrile molecules start to get in the way.

By forcing themselves between water molecules, they break the relatively strong hydrogen bonds between water molecules without replacing them by anything as good. This makes the process energetically less profitable, and so solubility decreases.

The hydrolysis of nitriles

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.

  1. 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.

   2. Alkaline Aydrolysis 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.

Reactions of Nitriles

Reaction type:  Nucleophilic Addition

Overview

• Nitriles typically undergo nucleophilic addition to give products that often undergo a further reaction.
• The chemistry of the nitrile functional group, CºN, is very similar to that of the carbonyl, C=O of aldehydes and ketones.Compare the two schemes:

        versus

• However, it is convenient to describe nitriles as carboxylic acid derivatives because:
• the oxidation state of the C is the same as that of the carboxylic acid derivatives.
• hydrolysis produces the carboxylic acid
• Like the carbonyl containing compounds, nitriles react with nucleophiles via two scenarios:

• Strong nucleophiles (anionic) add directly to the CºN to form an intermediate imine salt that protonates (and often reacts further) on work-up with dilute acid.

            Examples of such nucleophilic systems are :  RMgX, RLi, RCºCM, LiAlH₄
 

• Weaker nucleophiles (neutral) require that the CºN be activated prior to attack of the Nu.

     This can be done using a acid catalyst which protonates on the Lewis basic N and makes the system more electrophilic.

 

            Examples of such nucleophilic systems are :  H₂O, ROH
 

The protonation of a nitrile gives a structure that can be redrawn in another resonance form that reveals the electrophilic character of  the C since it is a carbocation.

Hydrolysis of Nitriles

Reaction type:  Nucleophilic Addition then Nucleophilic Acyl Substitution

Summary

• Nitriles, RCºN, can be hydrolyzed to carboxylic acids, RCO₂H via the amide, RCONH₂.
• Reagents : Strong acid (e.g. H₂SO₄) or strong base (e.g. NaOH) / heat.

Related Reactions

• Hydrolysis of Esters and Amides 

MECHANISM OF THE ACID CATALYZED HYDROLYSIS OF NITRILES
Step 1: An acid/base reaction. Since we only have a weak nucleophile so activate the nitrile, protonation makes it more electrophilic.
Step 2: The water O functions as the nucleophile attacking the electrophilic C in the CºN, with the electrons moving towards the positive center.
Step 3: An acid/base reaction. Deprotonate the oxygen that came from the water molecule. The remaining task is a tautomerization at N and O centers.
Step 4: An acid/base reaction. Protonate the N gives us the -NH2 we need
Step 5: Use the electrons of an adjacent O to neutralise the positive at the N and form the p bond in the C=O.
Step 6: An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the amide intermediate....halfway to the acid.....

 

Reduction of Nitriles

Reactions usually in Et₂O or THF followed by H₃O⁺ work-up 

Reaction type: Nucleophilic Addition

Summary

• The nitrile, RCºN, gives the 1^o amine by conversion of the CºN to -CH₂-NH₂
• Nitriles can be reduced by LiAlH₄ but NOT the less reactive  NaBH₄
• Typical reagents :  LiAlH₄  / ether solvent followed by aqueous work-up.
• Catalytic hydrogenation (H₂ / catalyst) can also be used giving the same products.
• R may be either alkyl or aryl substituents

Reactions of RLi or RMgX with Nitriles

Reaction usually in Et₂O or  THF 

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

Summary:

• Nitriles, RCºN, react with Grignard reagents or organolithium reagents to give ketones.
• The strongly nucleophilic organometallic reagents add to the CºN bond in a similar fashion to that seen for aldehydes and ketones.
• The reaction proceeds via an imine salt intermediate that is then hydrolyzed to give the ketone product.

• Since the ketone is not formed until after the addition of water, the organometallic reagent does not get the opportunity to react with the ketone product.
• Nitriles are less reactive than aldehydes and ketones.
• The mechanism is an example of the reactive system type

REACTION OF RMgX WITH AN NITRILE
	Step 1: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar nitrile group. Electrons from the CºN move to the electronegative N creating an intermediate imine salt complex.
	Step 2: An acid/base reaction. On addition of aqueous acid, the intermediate salt protonates giving the imine.
	Step 3: An acid/base reaction. Imines undergo nucleophilic addition, but require activation by protonation (i.e. acid catalysis)
	Step 4: Now the nucleophilic O of a water molecule attacks the electrophilic C with the p bond breaking to neutralize the change on the N.
	Step 5: An acid/base reaction. Deprotonate the O from the water molecule to neutralize the positive charge.
	Step 6: An acid/base reaction. Before the N system leaves, it needs to be made into a better leaving group by protonation.
	Step 7: Use the electrons on the O in order to push out the N leaving group, a neutral molecule of ammonia.
	Step 8: An acid/base reaction. Deprotonation reveals the carbonyl group of the ketone product.