Quiz Chapter 1

1. Certain C-H bonds have significantly lower bond dissociation energies than do the normalC-H bonds in saturated hydrocarbons. Offer a structural rationalization of the lower bond energy in each of the following compounds, relative to the saturated hydrocarbon C-H bond taken as a reference. (The bond dissociation energies are given in kcal/mol)
CH2 H (85) versus H3C H (103)

a.

b.

H 3C C O

(88)

versus

H 3C CH 2

(98)

Chapter 2 Stereochemical Principles

Introduction
Each individual molecular assembly => isomer Particular combinatin of bonds and sequence of atoms (molecular connectivity) which is characteristic of that structure => constitution Structure of the same constitution differ in spatial arrangement => Stereoisomers To specify stereoisomers => Configuration Two stereoisomers that are related by being nonsuperimposable mirror images => Enantiomer

 Structures that have nonsuperimposable mirror images => chiral Property of any molecule (or other object) of being nonsuperimposable on its mirror image=> enantiomerically pure or homochiral Samples containing an excess of one enantiomer over the other show a net rotation => optically active Samples that have equal amaounts of two enantiomers show zero rotation=> racemic mixtures Discrete molecular arrangements that differ in spatial arrangement as aresult of facile rotation about single bond=> conformation

Enantiomeric Relationships
Measurement of optical activity is useful for determining the configuration of chiral molecules and for investigating the stereochemical relationship between reactants and products

Optical Rotation
By convention, single-wavelenght measurements are usually made at the 589 nm emission line of sodium arc lamps This wavelenght is known as sodium D line Optical rotations measured at this wavelenght are designated []D

 Optical Rotation Dispersion (ORD)

Measurements of rotation as a function of wavelenght is useful in structural studies aimed at determining the chirality of a molecule This technique is called an ORD curve The shape of the ORD curve is determined by the configuration of the molecule and its absorption spectrum

 Circular Dischrosim (CD)

Enantiomeric substances also show differential absorption of circularly polarized-light. This is called circular dischroism (CD)

Where L and D are the extinction coefficient of left and right circularly polarized light

 Other Methods

Other methods for determining optical purity and assigning configuration => HPLC and GLC

Chiral Compound
Is a molecule having a single carbon atom with four nonidentical ligands This type of carbon is called asymmetric carbon since the molecular environment possesses no element of symmetry

 A number of types of compounds that are not superimposable on its mirror image: 1. Sulfoxide are nonplanar and there is a sufficient barrier to inversion as sulfur that pyramidal sulfoxide maintain their configuration at r.t. 2. Sulfonium salts with three non identical ligands are also chiral as a result of their pyramidal shape 3. Although unsymmetrically substituted amines are chiral, the configuration is not stable because of rapid inversion at nitrogen 4. The activation energy for pyramidal inversion at phosphorus is much higher that at nitrogen

5. The barrier of inversion is in the range of 30-35 kcal/mol so that enantiomerically pure phosphines are stable ar r.t. but racemized by inversion at elevated temperature.

Chan-Ingold-Prelog Convention
To specify the configuration of a chiral molecule Descriptors: R/S

Fisher Convention
To specify the configuration of a chiral molecule Descriptors: D/L

Diastereomeric Relationships
Diastereomers are defined as stereoisomers that are not related as an object and its mirror image Diastereoisomers differ in both physical properties and chemical reactivity They have different melting points, boiling points, solubility characteristics, etc. The specific rotations can differ in both magnitude and sign

Meso form
Compounds that contain asymmetric carbons but are nevertheless achiral
A plane of symmetry exist

Resolution
Diastereomic relationships provide the basis on which a range of chemical and physical separation processes occur Resolution/separation is frequently effected by converting the mixture of enantiomers into a mixture of diastereomers by reaction with a pure enantiomer of a second reagent (resolving agent)

Kinetic Resolution
An alternative means of resolution depends on the difference in rates of reaction (transition state energies) of two enantiomers with a chiral reagent This is because the two transition states (Rsubstrate---R-reactant) and (S-substrate---Rreactant) are diastereomeric Kinetic resolution is the term used to describe the separation of enantiomers by selective reaction with an optically pure reagent

 The greater the difference in the two rates, the higher will be the ennatiomeric purity of both the reacted and the unreacted enantiomer

Chiral Catalyst
Is also based on differences in transition state energies The intermediates and complexes containing enantiomeric reactant and a homochiral catalyst are diastereomeric and differ in energy E.g Enzymes Since enzyme catalysis is usually based on a specific fit to an active site, the degree of selection between the two enantiomers is often very high

Chromatography
Depend upon the difference between two enantiomers in noncovalent binding to a chiral substance This the basis for resolution by chromatography on homochiral adsorbents The noncovalent binding between enantiomers and the chromatographic adsorbent establises diastereomeric complexes and these have differing binding affinities

 This means that the two enantiomers will move through the column at different rates and can be separated Chiral column: OH group of the silica is covalently bonded to R-phenylglycine Method: conventional column chromatography, HPLC, GLC.

NMR
NMR spectroscopy provide one of the most convenient ways of detecting and quantitating the two diastereomeric products A pure enantiomer will give only a single spectrum The most widely used derivatizing reagent for the NMR method is a compound known as Moshers reagent

 Changes in NMR spectra can also be observed as the result of formation of noncovalent complexes between chiral molecules and another chiral reagent

Stereochemistry of Dynamic processes

Stereospecific reaction is one in which stereoisomeric starting materials afford stereisomerically different products under the same reaction conditions Stereoselective reaction is one in which a single reactant has the capacity of forming two or more stereoisomeric products in a particular reaction but one is formed preferentially

 Retention of configuration applies to a process in which the relative spatial arrangement at the reaction centre is the same in the reactant and the product Inversion of configurationdescribes a process in which the topology of the substitution site in the product has a mirror image relationship to that of the reactant Racemization describe any process which leads to formation of both configurations at a chiral centre and is not restricted to processes which involve bond cleavage

Stereoselective reactions

 Examples of Racemization: Pyramidal inversion at trivalent nitrogen, sulfur or phosphorus. The rate depends upon the barrier to the inversion process For ammonia and simple amines: the barrier is very low and inversion of configuration at nitrogen is rapid at room temperature, the racemization is too rapid to allow separation of enantiomer

Prochiral Relationships
The two protons at C-2 are therefore topologically equivalent and are termed homotopic ligands

 The two protons at C-1 are topologycally nonequivalent since substitution of one produces a product hat is stereochemically distinct from that produced by substitutions of the other. Ligands of this type are termed heterotopic or enantiotopic Both C-1 and C-3 are prochiral centres

 Pro R and Pro S The assignment is done by selecting one of the heterotopic ligands at the prochiral centre and arbitrarily assigning it a higher priority than the other without disturbing the priorities of the remaining ligands

 Prochiral faces Re (Rectus) and Si (Sinister) Addition of a fourth ligand, different from the three already present, to the carbonyl carbon of acetaldehyde will produce a chiral molecule If the substituents viewed from a particular face appear clockwise i order of decreasingpriority, then that face is re; if counterclockwise, then si

 Enantiotopic Processes which create an excess of one enantiomer of a pair

 Diastereotopic If each of two nominally equivalent ligands in a molecule is replaced by a test group and the molecules that are generated are diatereomeric

THE END