Organic Chemistry II

Fischer Projections
Fischer Projections are abbreviated structural forms that allow one to convey valuable stereochemical information to a chemist without them having to draw a 3D structural representation of a molecule. These representations are only used for molecules that contain chirality centers, which are then represented as simple crosses.

They can be derived by considering the more accurate 3D representation using wedges and assuming the convention that horizontal lines represent bonds coming out of the plane of the paper and vertical lines represent bonds going behind the plane of the paper.









When relating one Fischer projection to another it may only be manipulated within the 2D plane in which it is drawn (that is it may not be rotated within 3D space), and only rotated a total a 180^o



Why can't you rotate it 90^o?  A 90^o rotation is equivalent to breaking bonds and exchanging two groups, which would result in the formation of the other enantiomer.

CAUTION Fischer projections are often confused with simpler Lewis diagrams.  Lewis diagrams, however, are not intended to give any stereochemical information! Fischer projections a can be used to describe molecules with more than one chirality center.
 


If a Fischer projection of this type can be divided into two halves that are mirror images than the molecule may be identified as a meso isomer.   



Assignment of the configuration at a chirality center, in a Fischer projection, is based on the same Cahn-Ingold-Prelog rules.
The safest method for assigning the configuration is probably to convert it to a wedge-hash diagram (as shown above)
Alternatively....

• Identify the chirality centers (most commonly an sp³ C with 4 different groups attached).
• If the group of lowest priority is placed on a vertical line, this means the lowest priority group is already positioned away from you as if you were looking along the C-(4) s bond
• Now assess the direction of high to low priority (1 to 3)
• If this is clockwise, then the center is R (Latin: rectus = right)
• If this is counter clockwise, then it is S (Latin: sinister = left)
• If the group of lowest priority is placed on a horizontal line, this means the lowest priority group is actually positioned towards you (so we have to be very careful)
• Now assess the direction of high to low priority (1 to 3)
• If this is clockwise, then the center is R (Latin: rectus = right)
• If this is counter clockwise, then it is S (Latin: sinister = left)
• BUT NOW SWITCH THE ASSIGNMENT (it's like looking at a glass clock face from opposite sides

Stereochemistry

The different types of isomers. Stereochemistry focuses on stereoisomers

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).

Stereochemistry and organic reactivity

One of the major differences between laboratory organic reactions (which generally take place free in solution) and biological organic reactions (which generally  take place within the very specific, ordered environment of an enzyme) involves the concepts of stereoselectivity and stereospecificity.  In a stereoselective reaction, one  stereoisomer is formed preferentially over other possible stereoisomers:

In section 14.1, we will learn about a reaction type in which a water molecule is ‘added’ to a double bond. 

In many cases, this reaction results in the formation of one, or possibly two new stereocenters, depending on the symmetry of the starting alkene double bond.  Nonenzymatic laboratory reactions of this type generally are not stereospecific – that is, they result in the formation of mixtures of different stereoisomers.  In contrast, a crucial aspect of enzyme-catalyzed biological chemistry is that reactions are almost always highly stereoselective, meaning that they result in the formation of only one specific stereoisomer.  For example, this water addition reaction occurs as part of the oxidation of fatty acids:

Enzymatic reactions are also highly stereospecific: this means that an enzyme ‘recognizes’ the stereochemistry of a substrate molecule and only catalyzes its reaction if the substrate stereochemistry is correct. 

The enzyme that catalyzes the alkylation of (S)-glycerol phosphate, for example, will not work at all with (R)-glycerol phosphate.

When we begin our study of how organic reactions are catalyzed by enzymes, the reasons for their remarkable stereoselectivity and stereospecificity will become apparent.

After reading the story about thalidomide at the beginning of our discussion of stereochemistry, you have a good appreciation for the importance of stereoisomerism in drug development.  It is much safer and more effective if a drug can be provided in stereochemically pure form, without the presence of other ineffective (and possibly dangerous) enantiomers or diastereomers. Drug that are obtained from nature are generally in stereochemically pure form to begin with, because they are synthesized in a living organism by a series of enzymatic reactions. Penicillin, with its three stereocenters and 8 possible stereoisomers, is a good example: as a product synthesized by specific enzymes in penicillum mold, it exists as a single stereoisomer.

Other chiral drugs must be synthesized by humans in the laboratory, where it is much more difficult to produce a single stereoisomer.  Medicinal chemists are working very hard to develop new laboratory synthetic techniques which will allow them to better control the stereochemical outcome of their reactions.  We will see one example of such a technique in section 16.10B.  In addition, many researchers are trying to figure out the enzymatic process by which living things produce useful chiral molecules, so that the enzymes involved may be put to use as in vitro synthetic tools.  This is important because, while it may be easy to obtain large quantities of penicillum mold, many other useful chiral compounds come from species that are difficult, or even impossible, to grow in the lab.

Nitriles

INTRODUCING NITRILES

This page explains what nitriles are and looks at their simple physical properties such as solubility and boiling points.

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

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Note:  Compounds like this are formed when aldehydes react with hydrogen cyanide. This is therefore the sort of branched nitrile that you are most likely to come across at this level.

Physical properties

Boiling points

The small nitriles are liquids at room temperature.

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

Note:  The majority of the data sheets I have looked at quote this boiling range for butanenitrile. I don't know why it doesn't seem to have a precise boiling point.

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.

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.

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(+)”

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 inesonance 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.

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.

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.