[MODEL ANSWER]

AR-7512

M. Pharm. (Second Semester) Examination, 2013

Advanced Pharmaceutical Chemistry – I

Paper: Second

Section A

1

(i). Statement is not correct. Trans-1,2-dicyclohexane is dissymmetric not assymmetric. The

molecule has a C2 axis, in the plane of the three carbon atoms, however, its mirror image is not

superimposable on the original. It is not asymmetric as it does not lack any symmetry element.

(ii). Mutarotation is the change in optical/specific rotation with time of a freshly prepared

solution of sugar.

(iii). It is the extra strain associated with the cyclic structure of a compound when compared

with a similar acyclic compound. The ring strain is a combination of angle strain and torsional

strain.

(iv). Any conformation that is neither staggered (groups are as far apart as possible) nor

eclipsed (groups are close together).

(v). Any pair of stereoisomers which are not mirror images (enantiomers).

(vi).

S.

No.

Meso Racemic forms

1 Meso compounds are achiral, even

though they have asymmetric (chiral)

carbon atoms.

Racemic forms are mixture, composed of

equimolar parts of two enantiomers.

2 Optically inactive Optically inactive (show zero rotation)

3 Plane or point of symmetry present

within the molecule, internally

compensated.

Plane or point of symmetry not present.

It is a mixture, designated as (±) or dl.

4 Cannot be resolved into optically active Can be resolved into enantiomers (resolution).

isomers.

(vii). Tropinone is formed.

(viii). Dissolving metal reductions are reduction reactions in which aromatic ring are reduced

by sodium (potassium or lithium) in liquid ammonia, usually in the presence of an alcohol (ethyl,

isopropyl or t-butyl alcohol). 1,4-addition of hydrogen take place and non-conjugated

cyclohexadienes are produced.

(ix). Substitution nucleophilic internal (allylic shift). When a molecule has in an allylic

position a leaving group capable of giving the SNi reaction, it is possible for nucleophile to

attack at the γ–position instead of α–position.

(x). Four stereoisomers are possible for 2-bromo-3-chlorobutane.

(xi). Ketones (Pinacolones) or aldehyde.

(xii). In cyclopentane, two puckered conformation envelope and half-chair are present. In

cyclooctane, 95:5 mixture of boat-chair and crown confornmations are present.

Section B

2

(a)

‗Dissymmetric‘ first appeared in the early 1820s (even before Pasteur was born) in French

scientific literature, and was used in crystallography and other circumstances. Its meaning was

‗dissimilar or different in appearance or lack of symmetry‘. Dissymmetric is an obsolete

synonym of chiral. Not equivalent to asymmetric, since dissymmetric or chiral entities may

possess Cn axes (n > 1).

―The term asymmetric (or asymmetry) has a slightly different connotation in the sense that an

asymmetric molecule is a chiral molecule, it lacks Cn axis also; i.e., all symmetry elements are

absent except for the trivial C1 axis‖.

Term Alternating axis of

symmetry

Simple axis of

symmetry

Optical activity

Symmetric Present May or may not be Inactive

present

Dissymetric Absent May or may not be

present

Usually active

Asymmetric Absent Absent Usually active

In the case of trans-1,2-dimethylcyclopropane, the molecular configuration contains a two-fold

simple axis of symmetry passing through C3 and mid-point of C1–C2 bond, but there is no

alternating axis of symmetry. So, trans-1,2-dimethylcyclopropane is dissymmetric.

On a closer scrutiny of its mirror image configuration they are not superposable and thus are

optically active.

In the case of 2-butanol, the molecular configuration is devoid of any elements of symmetry (i.e.,

no Sn or Cn), except C1 which is a trivial one. 2-butanol can be described as either

dissymmetric or asymmetric. It appears that all asymmetric molecules are dissymmetric, but the

reverse is not true as dissymmetric trans-1,2-dimethylcyclopropane possessing only two-fold

simple axis of symmetry cannot be illustrated as asymmetric.

(b)

Racemic modification also called racemic mixtures or racemates, is an equimolecular mixture of

a pair of enantiomers (both levorotatory and dextrorotatory isomers), i.e., (+) – and (–) – forms

and is denoted by Racemic mixture is generally obtained in the following two

ways.

(i) By mixing equal amounts of the two enantiomers.

(ii) By synthesis. The synthesis of a chiral compound from achiral compound in the absence of

optically active agent or circularly polarised light always produces a racemic modification. For

example, the formation of lactonitrile from acetaldehyde always results in a racemic

modification in the following manner:-

Separation of dl–mixture of a compound into d and l isomers is known as resolution. This can be

done by several methods, viz. mechanical, biochemical and chemical method. Chemical method

involves the formation of diastereomers and is found to be the best method for resolution.

METHODS OF SEPARATION OF ENANTIOMERS

The first successful attempt to resolve enantiomers from their racemic mixture was performed by

Louis Pasteur, in which he manually resolved a racemic mixture of sodium ammonium tartrate

into its individual enantiomers (Pasteur, 1848). A multitude of methods and techniques for the

separation of enantiomers exists, though not all methods are equally applicable for every racemic

mixture. The main groups of techniques for the separation of enantiomers are schematized as

follows.

Chromatographic Separation Methods

The most common method to date for the enantiomeric resolution of chiral materials in general is

high performance liquid chromatography. For the direct separation of enantiomers by

chromatography on chiral stationary phases (CSP), two strategies are essentially applicable. The

first strategy consists of selecting the best available CSP for the racemic compound of interest,

while the second option consists of modifying (derivatizing) the racemic solute to accommodate

it to a defined CSP until it separates on this particular CSP. Construction of a chiral stationary

phase or prederivatization of the individual enantiomers to produce the diastereisomeric pair are

the two important techniques employed. Though these techniques vary from normal to reverse

phase and utilize a variety of detector systems.

Physical Separation Methods

Crystallization has been the predominant separation technique to resolve an enantiomeric

mixture into its individual isomers on the industrial scale. There are three primary methods of

crystallization for enantiomeric resolution

1. Preferential crystallization or resolution by entrainment – stereospecific growth of each

individual isomer in two different crystallizers from solution. This process requires no resolving

agent.

2. Diastereoisomeric crystallization – the resolving agent binds to enantiomers to a

diastereoisomeric salt pair. These salts are separated as a function of their phase behavior.

3. Catalytic kinetic resolution – the resolving agent reacts at a different rate with each

enantiomer.

The most attractive method involves the formation of diastereisomeric salts between acids and

bases and, in this case, the resolving agent can be readily removed and recycled.

Diastereoisomeric crystallization has been the dominant technique among industrial

pharmaceutical companies. This method is often referred to as classical resolution.

Enzymatic Kinetic Resolution

Two types of enzyme that have received increasing attention in the context of organic synthesis

are esterases and lipases. Lipases are a special example of carboxyl esterases. The main sources

of commercial lipases are porcine pancreas and a variety of bacteria and yeast. The extracellular

microbial lipases are particularly suited to synthetic applications because they have broad

substrate specificities and no coenzyme requirement for catalysis. Although the natural substrates

of lipases are acylglycerols, they can also catalyze the hydrolysis of a wide range of artificial

water-insoluble esters with a high degree of enantiospecificity. In low-water media, lipases

catalyze esterification, transesterification, and interesterification. These transformations can be

employed for the kinetic resolution of different chiral compounds.

The advantage of the enzymatic method is the high enantiomeric excess, resulting from the

inherent selectivity of the enzyme. The enzyme is reusable and the products of the reaction are

easy to separate. The disadvantages of this method are related to the number of parameters that

must be optimized for the enzyme and the selectivity of the system is limited by the extent of

conversion.

OTHER METHODS

Further techniques have been researched as potential methods for the preparation of optically

pure compounds. Gas chromatography-mass spectrometry, electrochromatography, capillary

electrophoresis and nuclear magnetic resonance have also been utilized as potential analytical

techniques in enantiomeric separation.

A recent development in the separation of ibuprofen enantiomers has been in supercritical fluid

chromatography. The most commonly used supercritical fluid is carbon dioxide, which has

chemical inertness and low toxicity.

3

A cyclohexane conformation is any of several three-dimensional shapes that it a assume while

maintaining the integrity of its chemical bonds. Cyclohexane ring tends to assume certain non-

planar conformations, which have all angles closer to 109° and therefore a lower strain energy

than the flat hexagonal shape. The most important shapes are called chair, half-chair, boat, and

twist-boat. The molecule can easily switch between these conformations, and only two of them

— chair and twist-boat — can be isolated in pure form.

Cyclohexane conformations have been extensively studied in organic chemistry because they are

the classical example of conformational isomerism and have noticeable influence on the physical

and chemical properties of cyclohexane.

The carbon-carbon bonds along the cyclohexane ring are sp³ hybrid orbitals, which have

tetrahedral symmetry. Therefore, the angles between bonds of a tetravalent carbon atom have a

preferred value θ ≈ 109.5°. The bonds also have a fairly fixed bond length λ. On the other hand,

adjacent carbon atoms are free to rotate about the axis of the bond. Therefore, a ring that is

warped so that the bond lengths and angles are close to those ideal values will have less strain

energy than a flat ring with 120° angles.

For each particular conformation of the carbon ring, the directions of the 12 carbon-hydrogen

bonds (and therefore the positions of the hydrogen atoms) are fixed.

There are exactly eight warped polygons with six distinguished corners that have all internal

angles equal to θ and all sides equal to λ. They comprise two ideal chair conformations, where

the carbons alternately lie above and below the mean ring plane; and six ideal boat

conformations, where two opposite carbons lie above the mean plane, and the other four lie

below it. In theory, a molecule with any of those ring conformations would be free of angle

strain. However, due to interactions between the hydrogen atoms, the angles and bond lengths of

the actual chair forms are slightly different from the nominal values. For the same reasons, the

actual boat forms have slightly higher energy than the chair forms. Indeed, the boat forms are

unstable, and deform spontaneously to twist-boat conformations that are local minima of the total

energy, and therefore stable.

Each of the stable ring conformations can be transformed into any other without breaking the

ring. However, such transformations must go through other states with stressed rings. In

particular, they must go through unstable states where four successive carbon atoms lie on the

same plane. These shapes are called half-chair conformations.

Chair conformation

The two chair conformations have the lowest total energy, and are therefore the most stable. In

the basic chair conformation, the carbons C1 through C6 alternate between two parallel planes,

one with C1, C3 and C5, the other with C2, C4, and C6. The molecule has a symmetry axis

perpendicular to these two planes, and is congruent to itself after a rotation of 120° about that

axis. The two chair conformations have the same shape; one is congruent to the other after 60°

rotation about that axis, or after being mirrored across the mean plane. The perpendicular

projection of the ring onto its mean plane is a regular hexagon. All C-C bonds are tilted relative

to the mean plane, but opposite bonds (such as C1-C2 and C4-C5) are parallel to each other.

As a consequence of the ring warping, six of the 12 carbon-hydrogen bonds end up almost

perpendicular to the mean plane and almost parallel to the symmetry axis, with alternating

directions, and are said to be axial. The other six C-H bonds lie almost parallel to the mean

plane, and are said to be equatorial.

The precise angles are such that the two C-H bonds in each carbon, one axial and one equatorial,

point in opposite senses relative to the symmetry axis. Thus, in a chair conformation, there are

three C-H bonds of each kind — axial "up", axial "down", equatorial "up", and equatorial

"down"; and each carbon has one "up" and one "down", and one axial and one equatorial. The

hydrogens in successive carbons are thus staggered so that there is little torsional strain.

The conversion from one chair shape to the other is called ring flipping or chair-flipping.

Carbon-hydrogen bonds that are axial in one configuration become equatorial in the other, and

vice-versa; but their "up" or "down" character remains the same.

Boat conformation

In the basic boat conformation, carbons C2, C3, C5 and C6 are coplanar, while C1 and C4 are

displaced away from that plane in the same direction. Bonds C2-C3 and C5-C6 are therefore

parallel. In this form, the molecule has two perpendicular planes of symmetry as well as a C2

axis. The boat conformations have higher energy than the chair conformations. The interaction

between the two flagpole hydrogens, in particular, generates steric strain. There is also torsional

strain involving the C2-C3 and C5-C6 bonds, which are eclipsed. Because of this strain, the boat

configuration is unstable (not a local minimum of the energy function).

Twist-boat conformation

The twist-boat conformation, sometimes called twist (D2 symmetry) can be derived from the

boat conformation by applying a slight twist to the molecule about the axes connecting the two

unique carbons. The result is a structure that has three C2 axes and no plane of symmetry.

The concentration of the twist-boat conformation at room temperature is very low (less than

0.1%) but at 1073 Kelvin it can reach 30%. Rapid cooling from 1073 K to 40 K will freeze in a

large concentration of twist-boat conformation, which will then slowly convert to the chair

conformation upon heating.

Half-chair conformation

The half-chair conformation is a transition state with C2 symmetry generally considered to be on

the pathway between chair and twist-boat. It involves rotating one of the dihedrals to zero such

that four adjacent atoms are coplanar and the other two atoms are out of plane (one above and

one below).

Interconversions between conformations

Twist-boat and chair are both energy minima—the twist-boat being a local minimum; the chair

being a global minimum (ground state).

The half-chair state (2, below) is the transition state in the interconversion between the chair and

twist-boat conformations. Due to the D2 symmetry of the twist-boat, there are two energy-

equivalent pathways that it can take to two different half-chair conformations, leading to the two

different chair conformations of cyclochexane. Thus, at a minimum, the interconversion between

the two chair conformations involves the following sequence: chair - half-chair - twist-boat -

half-chair' - chair'. The conformations involve following order of stability: chair form > twist

boat form > boat form > half-chair form. The boat conformation (4, below) is also a transition

state, allowing the interconversion between two different twist-boat conformations.

Conformational Analysis of Monosubstituted Cyclohexanes

The ring inversion, or ring flipping, that occurs in a molecule of cyclohexane takes place

between two equivalent conformations. Thus, when a cyclohexane molecule flips between chair

forms, the energy level for both forms is the same. However, if there is a substituent on the ring,

the number of molecules in each conformation is different because the conformations are no

longer equivalent. For example, if a hydrogen of cyclohexane is replaced with a methyl group to

form methylcyclohexane, the two chair forms are different. In one the methyl group is equatorial,

and in the other, it is axial.

The two chair forms are not present in equal amounts. Experimental evidence shows that at room

temperature approximately 95% of the methyl groups are equatorial. This preponderance is due

to the differences in stability of the two conformations. In any equilibrium process, the most

stable chemical species is present in greater quantities, and the chair form of methylcyclohexane

having the equatorial methyl group is the more stable one.

This distance is less than the sum of the van der Waals radii for two hydrogens (240 pm), so the

axial conformation of methylcyclohexane is destabilized by the strain of the van der Waals

repulsive forces. The van der Waals repulsive forces arise when the electron clouds surrounding

the atoms get close enough to repel one another.

Now rotate the methyl group to the equatorial position. Here all the hydrogens are in the axial

positions, and the distance between them is about 400 pm, much greater than the combined van

der Waals radii.

The stability of cyclohexanes having other axial substituents depends on the size of the

substituent. For example, for fluorocyclohexane, about 40% of the molecules have fluorine in the

axial position. When the substituent is an isopropyl group, about 3% of the molecules have the

substituent in the axial position. This percentage is so similar to that for the methyl substituent

that it might at first seem surprising because the isopropyl group is larger than the methyl group.

However, the isopropyl group orients itself so that a hydrogen points toward the axial hydrogens

on C3 and C5.

Conformational Analysis of Disubstituted Cyclohexanes

When a cyclohexane ring bears two substituents, the substituents occupy positions that are either

on the same side or on opposite sides of the ring. To help yourself visualize this positioning,

make molecular models of two cyclohexane rings and four methyl groups. Rotate both

cyclohexane rings into the chair conformation. Choose a back carbon on one of the rings and call

it C1. Replace the equatorial hydrogen on C1 with one of the methyl groups. Move to C2 and

replace the axial hydrogen on that carbon with a methyl substituent. Both substituents are on the

same side of the ring—one in the equatorial position and the other in the axial position.

Because both substituents are on the same side of the ring, they are cis to each other. Flip your

molecular model of cis-1,2-dimethylcyclohexane into the other chair conformation. Note that the

methyl group on C1 is now in the axial position, and the methyl group on C2 is in the equatorial

position.

When two substituents on adjacent carbons in cyclohexane are cis, one is always axial and the

other is always equatorial in either of the chair dimethylcyclohexane, both methyl groups point

up from the carbon ring—straight up for the axial methyl and slightly up for the equatorial

methyl, (Or, if you turn the model upside down, they both point down from the carbon ring).

Now take the other molecular model of cyclohexane. Locate one of the carbons, call it C1, and

replace the equatorial hydrogen with a methyl group. Move to C2, and replace the equatorial

hydrogen there with another methyl group. Note that both methyl groups are equatorial but on

opposite sides of the ring, or in the trans conformation.

Chemistry

Reactions

Pure cyclohexane in itself is rather unreactive, being a non-polar, hydrophobic hydrocarbon. It

can react with very strong acids such as the superacid system HF + SbF5, which will cause

forced protonation and "hydrocarbon cracking". Substituted cyclohexanes, however, may be

reactive under a variety of conditions, many of which being important to organic chemistry.

Cyclohexane is highly flammable.

Derivatives

The specific arrangement of functional groups in cyclohexane derivatives, and indeed in most

cycloalkane molecules, is extremely important in chemical reactions, especially reactions

involving nucleophiles . Substituents on the ring must be in the axial formation to react with

other molecules. For example, the reaction of bromocyclohexane and a common nucleophile, a

hydroxide anion (OH−), would result in cyclohexane.

C6H11Br + OH− → C6H10 + H2O + Br

−

This reaction, commonly known as an elimination reaction or dehalogenatio (specifically E2),

requires that the bromine substituent be in the axial formation, opposing another axial H atom to

react. Assuming that the bromocyclohexane was in the appropriate formation to react, the E2

reaction would commence as such:

1. The electron pair bond between the C-Br moves to the Br, forming Br− and setting it free

from cyclohexane

2. The nucleophile (-OH) gives an electron pair to the adjacent axial H, setting H free and

bonding to it to create H2O

3. The electron pair bond between the adjacent axial H moves to the bond between the two

C-C making it C=C

4

A chiral molecule is that cannot be transformed to itself with any mirror transformation. An

achiral molecule can be transformed to itself with a mirror transformation. Chiral molecules are

important because they are optically active in the sense that they can rotate the plane of polarized

light passing through the molecular sample. Optical activity can also result from lack of

molecular symmetry and molecules which do not have stereocenters, such as biphenyls, can also

be optically active. Chirality may be defined in two ways: a molecule is described as chiral if it

cannot be superimposed on its mirror reflection, or alternatively, if it does not possess an

alternating axis of symmetry (rotation reflection axis, Sn).

A molecule may be chiral only if it does not have an alternating axis of symmetry (Sn). Note, that

the molecule with a center of inversion i belongs to S2 group and thus cannot be chiral. Similarly,

because S1 = σ, any molecule with a mirror plane is achiral.

Dissymmetric is an obsolete synonym of chiral. Not equivalent to asymmetric, since

dissymmetric or chiral entities may possess simple or proper axis of symmetry, Cn axes (n > 1).

―The term asymmetric (or asymmetry) has a slightly different connotation in the sense that an

asymmetric molecule is a chiral molecule, it lacks Cn axis also; i.e., all symmetry elements are

absent except for the trivial C1 axis‖.

Term Alternating axis of

symmetry

Simple axis of

symmetry

Optical activity

Symmetric Present May or may not be

present

Inactive

Dissymetric Absent May or may not be

present

Usually active

Asymmetric Absent Absent Usually active

In the case of trans-1,2-dimethylcyclopropane, the molecular configuration contains a two-fold

simple axis of symmetry passing through C3 and mid-point of C1–C2 bond, but there is no

alternating axis of symmetry. So, trans-1,2-dimethylcyclopropane is dissymmetric. On a closer

scrutiny of its mirror image configuration they are not superposable and thus are optically active.

In the case of 2-butanol, the molecular configuration is devoid of any elements of symmetry (i.e.,

no Sn or Cn), except C1 which is a trivial one. 2-butanol can be described as either

dissymmetric or asymmetric. It appears that all asymmetric molecules are dissymmetric, but the

reverse is not true as dissymmetric trans-1,2-dimethylcyclopropane possessing only two-fold

simple axis of symmetry cannot be illustrated as asymmetric.

Axo-dissymmetry: dissimilar from axis of symmetry

Axis of symmetry is of two types: 1) a simple or proper axis of symmetry (Cn) and 2) alternating

axis of symmetry (rotation reflection axis, Sn).

A simple or proper axis of symmetry (Cn)

When an imaginary line (axis) can be drawn through a molecule so that rotation by 360o/n gives

the molecule indistinguishable from the original, then that molecule is said to have rotation axis

(Cn of order n, also called n-fold axis).

Examples:

(E)-1,2-dichloroethane 2-fold axis of symmetry (C2)

Boron trifluoride (BF3) 3-fold axis of symmetry (C3)

Benzene 6- fold axis of symmetry (C6)

If a rotation by 360o/n of a molecule through an imaginary axis-gives a molecule identical with

the original it is said to have n fold simple axis of symmetry.

1,3-substituted cyclobutane has a twofold axis C2 and the cis-tetrasubstituted cyclobutane has a

C4 axis. The presence of the Cn does not preclude chirality. Chirality, therefore, can not be

equated with total asymmetry.

The 2-fold axis C2 changes the sign of two coordinates only, e.g. the axis that runs colinearly

with the z axis converts A(x,y,z) into A(-x,-y,z).

Examples of molecules with an axis of symmetry only:

Examples of molecules with axis of symmetry and a coaxial plane of symmetry

Alternating axis of symmetry (rotation reflection axis, Sn)

A molecule is said to possess an n-fold alternating axis of symmetry if rotation through an angle

of 360o/n about this axis and then followed by reflection in a plane perpendicular to the axis,

gives a molecule which is indistinguishable from the original molecule.

Since a one fold alternatin g axis corresponds to a plane of symmetry, and a two fold alternating

axis corresponds to a centre of symmetry, therefore, absence of alternating axis of symmetry is

the necessary and sufficient condition for a molecule to exhibit optical activity.

Centre of dissymmetry: dissimilar form the center of symmetry.

Center of Symmetry

Center of symmetry or inversion center, abbreviated i. A molecule has a center of symmetry

when, for any atom in the molecule, an identical atom exists diametrically opposite this center an

equal distance from it. There may or may not be an atom at the center. Examples are xenon

tetrafluoride where the inversion center is at the Xe atom, and benzene (C6H6) where the

inversion center is at the center of the ring.

The center of symmetry i is a point in space such that if a line is drawn from any part (atom) of

the molecule to that point and extended an equal distance beyond it, an analogous part (atom)

will be encountered.

An example of point of symmetry is 1,3-trans-disubstituted cyclobutane, below. Note that the

chiral G substituent is inverted on both sides of the point of symmetry. This symmetry element is

sometimes also called "the point of inversion".

Point of symmetry placed at the origin of Cartesian coordinate system converts point A(x,y,z)

into A'(-x,-y,-z). Molecules which have a center of symmetry are achiral, even though they may

have chiral fragments in them.

Examples:

Plane of Symmetry

Planes, centers and alternating axes correspond to "symmetry operations of the second kind"

or "improper operations" since they bring into coincidence the material point of an object with

its mirror reflection.

A plane of symmetry is a reflection plane which brings into coincidence one point of the

molecule with another one through the mirror reflection.

In contrast to the center of symmetry, a plane of symmetry converts A(x,y,z) into A'(-x,y,z),

A'(x,-y,z) or A'(x,y,-z), depending which of the cartesian planes, yz, xz, or xy, respectively, is a

plane of symmetry.

A plane of symmetry precludes chirality, i.e. molecules featuring are achiral. Examples of

molecules with a plane of symmetry only:

Most aromatic drugs without attached chiral chains have only a plane of symmetry.

Examples of molecules with a plane of symmetry and n-fold perpendicular axis of symmetry:

5

Hofmann rearrangement

The Hofmann rearrangement is the organic reaction of a primary amide to a primary amine with

one fewer carbon atom.

The reaction is named after its discoverer: August Wilhelm von Hofmann. This reaction is also

sometimes called the Hofmann degradation.

The reaction of bromine with sodium hydroxide forms sodium hypobromite in situ, which

transforms the primary amide into an intermediate isocyanate. The intermediate isocyanate is

hydrolyzed to a primary amine, giving off carbon dixide.

Several reagents can substitute for bromine. N-Bromosuccinimide and 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) can effect a Hofmann rearrangement. In the following

example, the intermediate isocyanate is trapped by methanol, forming a carbamate.

In a similar fashion, the intermediate isocyanate can be trapped by tert-butanol, yielding the t-

butoxycarbonyl (Boc)-protected amine.

A mild alternative to bromine is also (bis(trifluoroacetoxy)iodo)benzene.

Applications

Aliphatic & Aromatic amides are converted into aliphatic and aromatic amines,

respectively

In the preparations of Anthranilic Acid from Phthalimide

Nicotinic acid is converted into 3-Amino pyridine

The Symmetrical structure of α-phenyl propanamide does not change after hofmann

reaction.

Meerwein-Ponndorf-Verley (MPV) Reduction

The Meerwein-Ponndorf-Verley (MPV) Reduction is the reduction of ketones and aldehydes

to their corresponding alcohols utilizing aluminium alkoxide catalysis in the presence of a

sacrificial alcohol. The beauty in the MPV reduction lies in its high chemoselectivity and its use

of a cheap environmentally friendly metal catalyst.

Exchange of carbonyl oxidation states in the presence of aluminium isopropoxide.

The MPV reduction was discovered by Meerwein and Schmidt, and separately by Verley in

1925. They found that a mixture of aluminium ethoxide and ethanol could reduce aldehydes to

their alcohols. Ponndorf applied the reaction to ketones and upgraded the catalyst to aluminium

isopropoxide in isopropanol.

Mechanism

The MPV reduction is believed to go through a catalytic cycle involving a six member ring

transition state as shown in Figure 2. Starting with the aluminium alkoxide 1, a carbonyl oxygen

is coordinated to achieve the tetra coordinated aluminium intermediate 2. Between intermediates

2 and 3 the hydride is transferred to the carbonyl from the alkoxy ligand via a pericyclic

mechanism. At this point the new carbonyl dissociates and gives the tricoordinated aluminium

species 4. Finally, an alcohol from solution displaces the newly reduced carbonyl to regenerate

the catalyst 1.

Catalytic Cycle of Meerwein-Ponndorf-Verley Reduction

Each step in the cycle is reversible and the reaction is driven by the thermodynamic properties of

the intermediates and the products. This means that given time the more thermodynamically

stable product will be favored.

Several other mechanisms have been proposed for this reaction, including a radical mechanism

as well as a mechanism involving an aluminium hydride species. The direct hydride transfer is

the commonly accepted mechanism recently supported by experimental and theoretical data.

Chemoselectivity

One of the great draws of the Meerwein–Ponndorf–Verley reduction is its chemoselectivity.

Aldehydes are reduced before ketones allowing for a measure of control over the reaction. If it is

necessary to reduce one carbonyl in the presence of another, the common carbonyl protecting

groups may be employed. Groups, such as alkenes and alkynes that normally pose a problem for

reduction by other means have no reactivity under these conditions.

Stereoselectivity

The aluminium based Meerwein-Ponndorf-Verley reduction can be performed on prochiral

ketones leading to chiral alcohols. The three main ways to achieve the asymmetric reduction is

by use of a chiral alcohol hydride source, use of an intramolecular MPV reduction, or use of a

chiral ligand on the aluminium alkoxide.

One method of achieving the asymmetric MPV reduction is with the use of chiral hydride

donating alcohols. The use of chiral alcohol (R)-(+)-sec-o-bromophen-ethyl alcohol gave 82%ee

(percent enantiomeric excess) in the reduction of 2-chloroacetophenone. This enantioselection is

due to the sterics of the two phenol groups in the six membered transition state as shown in

Figure 3. In Figure 3, 1 is favored over 2 due to the large steric effect in 2 from the two phenyl

groups.

Transition states of MPV reduction with a chiral alcohol

The use of an intramolecular MPV reduction can give good enantiopurity. By tethering the

ketone to the hydride source only one transition state is possible leading to the asymmetric

reduction. This method, however, has the ability to undergo the reverse Oppenauer oxidation due

to the proximity of the two reagents. Thus the reaction runs under thermodynamic equilibrium

with the ratio of the products related to their relative stabilities. After the reaction is run the

hydride-source portion of the molecule can be removed.

Transition state of intramolecular MPV reduction

Chiral ligands on the aluminium alkoxide can effect the stereochemical outcome of the MPV

reduction. This method lead to the reduction of substituted acetophenones in up to 83% . The

appeal of this method is that it uses a chiral ligand as opposed to a stoiciometric source of

chirality. It has been recently shown that the low selectivity of this method is due to the shape of

the transition state. It has been shown that the transition state is a planar six member transition

state. This is different than the believed Zimmerman-Traxler model like transition state.

MPV reaction with chiral ligand

6

Hofmann elimination, also known as exhaustive methylation, is a process where an amine is

reacted to create a tertiary amine and an alkene by treatment with excess methyl iodide followed

by treatment with silver oxide, water and heat.

After the first step, a quaternary ammonium iodide salt is created. After replacement of iodine by

an hydroxyl anion, an elimination reaction takes place to the alkene.

With asymmetrical amines, the major alkene product is the least substituted and generally the

least stable, an observation known as the Hofmann rule. This is in direct contrast to normal

elimination reactions where the more substituted, stable product is dominant (Zaitsev's rule).

The reaction is named after its discoverer, August Wilhelm von Hofmann. An example is the

synthesis of trans-cyclooctene.

Saytseff Elimination: elimination reactions occurring according to the Saytseff's Rule.

Zaitsev's Rule (or Saytseff's Rule) is an empirical rule for predicting the favored alkene

product(s) in elimination reactions. Russian chemist Alexander Zaitsev studied a variety of

different elimination reactions and observed a general trend in the resulting alkenes. Based on

this trend, Zaitsev stated, "The alkene formed in greatest amount is the one that corresponds to

removal of the hydrogen from the β-carbon having the fewest hydrogen substituents." For

example, when 2-iodobutane is treated with alcoholic KOH, 2-butene is the major product and

1-butene is the minor product.

More generally, Zaitsev's rule predicts that in an elimination reaction, the most stable alkene -

typically the most substituted one - will be the favored product. While effective at predicting the

favored product for many elimination reactions, Zaitsev's rule is subject to many exceptions.

Thermodynamic considerations

The hydrogenation hydrogenation of alkenes to alkanes is exothermic. The amount of energy

released during a hydrogenation reaction, known as the heat of hydrogenation, is inversely

related to the stability of the starting alkene: the more stable the alkene, the lower its heat of

hydrogenation. Examining the heats of hydrogenation for various alkenes reveals that stability

increases with the amount of substitution.

Compound Name Structure Molar Heat of Hydrogenation

Degree of Substitution in kj/mol in kcal/mol

Ethylene

137 32.8 Unsubstituted

1-Butene

127 30.3 Monosubstituted

trans-2-Butene

116 27.6 Disubstituted

2-Methyl-2-butene

113 26.9 Trisubstituted

2,3-Dimethyl-2-butene

111 26.6 Tetrasubstituted

The increase in stability associated with additional substitutions is the result of several factors.

Alkyl groups are electron donating, and increase the electron density on the π bond of the alkene.

Also, alkyl groups are sterically large, and are most stable when they are far away from each

other. In an alkane, the maxiumum separation is that of the tetrahedral bond angle, 109.5°. In an

alkene, the bond angle increases to near 120°. As a result, the separation between alkyl groups is

greatest in the most substituted alkene.

Hyperconjugation, which describes the stabilizing interaction between the HOMO of the alkyl

group and the LUMO of the double bond, also helps explain the influence of alkyl substitutions

on the stability of alkenes. In regards to orbital hybridization, a bond between an sp2 carbon and

an sp3carbon is stronger than a bond between two sp

3-hybridized carbons. Computations reveal a

dominant stabilizing hyperconjugation effect of 6 kcal/mol per alkyl group.

Steric effects

In E2 elimination reactions, a base abstracts a proton that is beta to a leaving group, such as a

halide. The removal of the proton and the loss of the leaving group occur in a single, concerted

step to form a new double bond. When a small, unhindered base- such as sodium hydroxide,

sodium methoxide or sodium ethoxide - is used for an E2 elimination, the Zaitsev product is

typically favored over the least substituted alkene, known as the Hofmann product. For example,

treating 2-bromo-2-methylbutane with sodium ethoxide in ethanol produces the Zaitsev product

with moderate selectivity.

Due to steric interactions, a bulky base – such as potassium t-butoxide, triethylamine or 2,6-

lutidine cannot readily abstract the proton that would lead to the Zaitsev product. In these

situations, a less sterically hindered proton is preferentially abstracted instead. As a result, the

Hofmann product is typically favored when using bulky bases. When 2-bromo-2-methylbutane is

treated with potassium t-butoxide instead of sodium ethoxide, the Hofmann product is favored.

Steric interactions within the substrate also prevent the formation of the Zaitsev product. These

intramolecular interactions are relevant to the distribution of products in the Hofmann

elimination reaction, which converts amines to alkenes. In the Hofmann elimination, treatment

of a quaternary ammonium iodide salt with silver oxide produces hydroxide ion, which acts as a

base and eliminates the tertiary amine to give an alkene.

In the Hofmann elimination, the least substituted alkene is typically favored due to

intramolecular steric interactions. The quaternary ammonium group is large, and interactions

with alkyl groups on the rest of the molecule are undesirable. As a result, the conformation

necessary for the formation of the Zaitsev product is less energetically favorable than the

conformation required for the formation of the Hofmann product. As a result, the Hofmann

product is formed preferentially. The Cope elimination is very similar to the Hofmann

elimination in principle, but occurs under milder conditions. It also favors the formation of the

Hofmann product, and for the same reasons.

Stereochemistry

In some cases, the stereochemistry of the starting material can prevent the formation of the

Zaitsev product. For example, when menthyl chloride is treated with sodium ethoxide, the

Hofmann product is formed exclusively:

This interesting result is due to the stereochemistry of the starting material. E2 eliminations

require anti-periplanar geometry, in which the proton and leaving group lie on opposite sides of

the C-C bond, but in the same plane. When menthyl chloride is drawn in the chair conformation,

it is easy to explain the unusual product distribution.

Formation of the Zaitsev product requires elimination at the 2-position, but the isopropyl group -

not the proton - is anti-periplanar to the chloride leaving group; this makes elimination at the 2-

position impossible. In order for the Hofmann product to form, elimination must occur at the 6-

position. Because the proton at this position has the correct orientation relative to the leaving

group, elimination can and does occur. As a result, this particular reaction produces only the

Hofmann product.

7

Nucleophilic aromatic substitution is a ubstitution reaction in which the nucleophile displaces

a good leaving group, such as a halide, on an aromatic ring. There are 6 nucleophilic substitution

mechanisms encountered with aromatic systems:

the SNAr (addition-elimination) mechanism

the aromatic SN1 mechanism encountered with diazonium salts.

the benzyne mechanism

the free radical SRN1 mechanism

the ANRORC mechanism

Vicarious nucleophilic substitution.

The most important of these is the SNAr mechanism, where electron withdrawing groups

activate the ring towards nucleophilic attack, for example if there are nitro functional groups

positioned ortho or para to the halide leaving group.

SNAr reaction mechanism

Aryl halides cannot undergo SN2 reaction .The C–Br bond is in the plane of the ring as the

carbon atom is trigonal. To attack from the back, the nucleophile would have to appear inside the

benzene ring and invert the carbon atom in an absurd way. This reaction is not possible.

SN1 reaction is possible but very unfavourable. It would involve the unaided loss of the leaving

group and the formation of an aryl cation.

The following is the reaction mechanism of a nucleophilic aromatic substitution of 2,4-

dinitrochlorobenzene in a basic aqueous solution.

In this sequence the carbons are numbered clockwise from 1-6 starting with the 1 carbon at 12

o'clock, which is bonded to the chloride. Since the nitro group is an activator toward

nucleophilic substitution, and a meta director, it allows the benzene carbon to which it is

bonded to have a negative charge. In the Meisenheimer complex, the nonbonded electrons of

the carbanion become bonded to the aromatic pi system which allows the ipso carbon to

temporarily bond with the hydroxyl group (-OH). In order to return to a lower energy state, either

the hydroxyl group leaves, or the chloride leaves. In solution both processes happen. A small

percentage of the intermediate loses the chloride to become the product (2,4-dinitrophenol),

while the rest return to the reactant. Since 2,4-dinitrophenol is in a lower energy state it will not

return to form the reactant, so after some time has passed, the reaction reaches chemical

equilibrium.

The formation of the resonance-stabilized Meisenheimer complex is slow because it is in a

higher energy state than the aromatic reactant. The loss of the chloride is fast, because the ring

becomes aromatic again.

Nucleophilic aromatic substitution reactions

Some typical substitution reactions on arenes are listed below.

In the Bamberger rearrangement N-phenylhydroxylamines rearrange to 4-aminophenols.

The nucleophile is water.

In the Sandmeyer reaction and the Gattermann reaction diazonium salts react with

halides.

The Smiles rearrangement is the intramolecular version of this reaction type.

Nucleophilic aromatic substitution is not limited to arenes, however; the reaction takes place

even more readily with heteroarenes. Pyridines are especially reactive when substituted in the

aromatic ortho position or aromatic para positio because then the negative charge is effectively

delocalized at the nitrogen position. One classic reaction is the Chichibabin reaction in which

pyridine is reacted with an alkali-metal amide such as sodium amide to form 2-aminopyridine.

In the compound methyl 3-nitropyridine-4-carboxylate, the meta nitro group is actually displaced

by fluorine with caesium fluoride in DMSO at 120°C.

Asymmetric nucleophilic aromatic substitution

With carbon nucleophiles such as 1,3-dicarbonyl compounds the reaction has been demonstrated

as a method for the asymmetric synthesis of chiral molecules. First reported in 2005, the

organocatalyst (in a dual role with that of a phase transfer catalyst) is derived from cinchonidine

(benzylatet at N and O).