Kamis, 14 Juni 2012

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.

Stereochemistry of Reactions

Many simple reactions involve stereochemistry.
A reaction that involves only achiral reactants and reagents can produce only racemic mixtures or products that are achiral. Thus, the monobromination of butane produces a mixture of 1-bromobutane and 2-bromobutane. The 1-bromobutane has no stereogenic center and is, therefore, achiral. The 2-bromobutane, which has a stereogenic center, is a mixture of the enantiomers ( R)-2-bromobutane and ( S)-2-bromobutane. This racemic mixture results because the reaction proceeds via a free-radical mechanism. Free radicals are almost perfectly planar. This planarity makes the product mixture achiral because there is equal probability of a bromine free radical attacking from either side of the carbon free radical intermediate.

Addition of a halogen atom to an alkene proceeds via a trans addition. This occurs due to steric hindrance created by the formation of the halonium ion.
Catalytic hydrogenation of alkenes and alkynes takes place via cis addition because absorption of the hydrogen on the surface of the rigid catalyst allows the hydrogen atoms to approach the double bond from only one side of the alkene molecule.
Dehydrohalogenation of chloroethane to form ethene proceeds via a trans elimination reaction because of the tetrahedral shape of the carbon atom bonded to the chlorine atom. To displace the chlorine as a chloride ion, the electron pair of the other carbon must approach from the unhindered side opposite the chlorine atom.

stereochemystry

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).

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.

Thalidomide example

An oft cited example of the importance of stereochemistry relates to the thalidomide disaster. Thalidomide is a drug, first prepared in 1957 in Germany, prescribed for treating morning sickness in pregnant women. The drug was discovered to be teratogenic, causing serious genetic damage to early embryonic growth and development, leading to limb deformation in babies. Some of the several proposed mechanisms of teratogenecity involve a different biological function for the (R)- and the (S)-thalidomide enantiomers. In the human body however, thalidomide undergoes racemization: even if only one of the two enantiomers is administered as a drug, the other enantiomer is produced as a result of metabolis^. Accordingly, it is incorrect to state that one of the stereoisomer is safe while the other is teratogenic. Thalidomide is currently used for the treatment of other diseases, notably cancer and leprosy. Strict regulations and controls have been enabled to avoid its use by pregnant women and prevent developmental deformations. This disaster was a driving force behind requiring strict testing of drugs before making them available to the public.

Definitions

syn/anti peri/clinal

Many definitions that describe a specific conformation (IUPAC Gold Book) exist:

a torsion angle of ±60° is called gauche
a torsion angle between 0° and ± 90° is called syn (s)
a torsion angle between ± 90° and 180° is called anti (a)
a torsion angle between 30° and 150° or between –30° and –150° is called clinal
a torsion angle between 0° and 30° or 150° and 180° is called periplanar (p)
a torsion angle between 0° to 30° is called synperiplanar or syn- or cis-conformation (sp)
a torsion angle between 30° to 90° and –30° to –90° is called synclinal or gauche or skew (sc)
a torsion angle between 90° to 150°, and –90° to –150° is called anticlinal (ac)
a torsion angle between ± 150° to 180° is called antiperiplanar or anti or trans (ap).

Torsional strain results from resistance to twisting about a bond.

Selasa, 12 Juni 2012

nomenclature 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

nucleophilic addition of aldehyes and ketones

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.

Addition of strong nucleophiles to nitriles

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.

Addition of weaker nucleophiles under acidic conditions to nitriles

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
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.....

The Nitriles

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.

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.

Note: If you aren't happy about intermolecular attractions then you really ought to follow this link before you go on. Use the BACK button on your browser to return to this page.

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.

Minggu, 10 Juni 2012

Synthesis of lactams

Synthesis of alpha-lactams

(CC) Image: David E. Volk
A general purpose alpha-lactam synthesis

The cyclization reaction of an $\alpha$ -haloamide precuror in the presence of sodium hydride and 15-crown-5 ether at room temperature in dichloromethane (CH₂Cl₂) is a high-yielding, general route to $\alpha$ -lactam (aziridinone) products. The hydrogen gas and sodium halide by-products are readily removed.^[1]

Antibiotics

(CC) Image: David E. Volk
Base structure of all cephalosporins.

The $\beta$ -lactam forms the center structure of many antibiotic drugs, such as the cephalosporins and the penicillins, as shown above. In the penicillins, the non-lactam ring is one atom smaller compared to the cephalosporins. The activity of cephalosporins, penicillins, and some other antibiotics are due to the presence of the beta-lactam, which binds irreversibly, via acylation, to penicillin-binding proteins, thereby inhibiting the peptidogycan layer of bacterial cell wall synthesis. Cephalosporins and penicillins are often made semi-synthetically, using a core structure obtained from a natural organism, such as a fungus, due to the difficulty and expense of synthesizing these lactams.
Beta-lactams are four-membered cyclic amides, best known for the penicillins based on a bicyclo-thiazolidine, as well as the cephalosporins based on a bicyclo-thiazine, and including monocyclic monobactams. The beta-lactamases hydrolyze the beta lactam ring, accounting for beta-lactam resistance of infective bacteria

Lactams the other definition

This issue of Enamine Product Focus highlights Lactams, cyclic amide building blocks. There are numerous examples of Lactams usage in drug discovery, e.g., β-lactam based antibiotics, oral anticoagulant Rivaroxaban, and anticonvulsant Levetiracetam.


Rivaroxaban, 2008	Levetiracetam, 2000

The specific features of Lactam building blocks that are of advantage to drug design are summarized in the chart below.

Enamine’s Lactam building block collection is represented by many useful scaffolds, for example, piperidones, piperazinones, (thio)morpholiones, pyrrolidones, and their benzo-fused analogues. From combinatorial chemistry standpoint especially interesting lactams in our collection are those bearing additional functionalities, such as carboxyl, chlorosulfonyl, and amino-groups.


Piperidones	Piperazinones	Morpholinones

Thiomorpholinones	Pyrrolidones	Dihydroquinoxalinones

The procedures developed for the synthesis of our Lactams allow preparation of highly diverse building blocks on 1–10 g scale. In addition we offer synthesis of novel compounds of the requested structure in 4–8 weeks. Scale-up to 1 kg quantity is performed upon request.

Representative examples of our Lactam building blocks are given below.