CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
Subject Chemistry
Paper No and Title 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No and Title 24: Stereoselective and Stereospecific Reactions
Module Tag CHE_P1_M24
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions TABLE OF CONTENTS
1. Learning Outcomes 2. Introduction
3. Diastereoselective and enantioselective reactions 3.1 Diastereoselective reactions
4. Summary
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 1. Learning Outcomes
After studying this module, you shall be able to
Know the stereoselective and stereospecific reactions
To know the diastereoselection in acyclic system
To predict diastereoselection in cyclic system
2. Introduction
2.1. What is Stereoselectivity and Stereospecificity?
One of the major objectives of a synthetic organic chemist is to synthesize an organic compound containing multiple chiral centres in a single specific stereoisomer. It is also desirable that the stereo chemical transformations be carried out in a predictable manner so that the synthesis can be used to establish the configuration of the molecule.
The stereochemistry at a chiral centre during a reaction is fixed either by conducting the reaction under kinetic control in which case the stereoselectivity depends on the difference in the free energies of the respective transition states or by carrying out the reaction under thermodynamic control in which case the Stereoselectivity depends on the difference in the free energies of the products.
Stereoselectivity
Stereoselectivity is the property of a reactant mixture where a non-stereospecific mechanism allows for the formation of multiple product, but where one (or a subset) of the product is favored by factors, such as steric access, that are independent of the mechanism.
Stereoselectivity is of great importance in the design of synthesis of natural products.
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions Stereospecificity
Stereospecificity is the property of a reaction mechanism, where, starting materials differing only in their configuration are converted into stereoisomeric products. Thus, a stereospecific process is necessarily stereoselective but not all stereoselective processes are stereospecific.
Stereospecificity may be total (100%) or partial. The term is also applied to situations where reaction can be performed with only one stereoisomer.
Stereoselective reactions
Stereoselective reactions yield predominantly one stereoisomer (or one pair of enantiomers) of the several diastereomers. It can also be defined as a reaction in which there is a choice of pathway, but the stereoisomeric product is formed due to its reaction pathway being more favorable than the others available. The elimination reaction of 2-iodobutane (1) in the presence of base (tBuOK) in DMSO gives three products trans-2-butene (2), cis-2-butene (3) and 1-butene (4). The major product formation is trans-2-butene (2) (Fig. 1.) so we can say this reaction is stereoselective because cis and trans alkenes are the diastereomers.
Another example of the addition of bromine to trans-2-butene (2) give a erytho-2,3- dibromobutane (5) as a product (Fig. 2). In this case the erythro product 5 is produced and not formed other threo diastereomers. So we can say this reaction is also diastereoselective.
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions Stereospecific reaction
As mentioned earlier, a reaction in which stereochemically different molecules reacts differently is called a stereospecific process. In this case the cis- and trans- stereoisomers give different products. A reaction in which the stereochemistry of the reactant completely determined by the stereochemistry of the product without any other options. The addition of carbene to cis-butene and trans-butene stereospecifically give the cis-1,2-dimethylcycopropane (7) and trans-1,2- dimethylcyclopropane (8), respectively (Fig. 3).
Principle of stereoselectivity
For a reaction to be stereoselective, the substrate must have prostereogenic elements, which in turn depends on the symmetry or more specially on the topicity of the reacting group or faces on appropriate modification give rise to stereoisomers (enantiomers and diastereomers). The principle of stereoselectivity whether it refers to diastereoselectivity or enantioselectivity in a
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
kinetically controlled reaction is the same. The two stereoisomers must be formed through two diastereomeric transitions. By virtue of their diastereomeric nature, they would differ in their free energies and thus give products in different amount. The greater is the difference in the free energy, the higher is the stereoselectivity. A difference of 10 kJ mol-1 at ambient temperature leads to the formation of the preferred isomer in about 98% yield. The stereoelectronic factor, the steric factor, and other electronic effects (including the participation of chelate and hydrogen bonds) are all to be considered in designing a highly stereoselective reaction. The strategy of such a synthesis has to be decided on an individual basis and no fixed guideline be given.
The principle of enantioselective reaction stated above is illustrated with the help of energy diagrams (Fig. 4). Acetophenone (9) has two enantiotopic faces Re and Si as shown and an organometallic hydride represented by H-M (L) (M = organic ligand or ligands) can approach the trigonal carbon from either face through two transition states TS-1 or TS-2. If L is equienergetic, R- and S- alcohols (10) are formed racemic mixture and enantioselectivity is non-existent (Fig.
5). But if L is chiral, the two transition states are no longer enantiomeric but diastereomeric. The stereoselectivity is achieved through the formation of the two diastereomeric transition states. It may be noted that the ground state energies of the products are the same so under thermodynamically controlled condition, the product would be racemic.
Fig. 4: Energy level diagram of an enantioselective reaction
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 3. Asymmetric synthesis and asymmetric induction
According to the original definition (Marckwald), an asymmetric synthesis is a reaction which produces optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with exclusion of any analytical process.
According to broader definition by Morrison and Mosher (1971), an asymmetric synthesis is a reaction in which an achiral unit in an ensemble of substrate molecules (having either enantiotopic or diastereotopic groups or faces) is converted into a chiral unit in such a manner that unequal amount of stereoisomers are produced. When the products are diastereomers, they may be either optically active or racemic. Confusion arises when reactions give two achiral diastereomers, e.g., reduction of 4-t-butylcyclohexanone (11) to cis- and trans-4-t- butylcyclohexanols (12) (Fig. 6). According to the above definition, this is not an asymmetric
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
synthesis but the analogous reduction of 2-methylcyclohexanone (13) is since an additional chiral centre is being created in the process and gives cis, trans-2-methylcyclohexanol (14) (Fig.
7). Asymmetric induction defines the extent of asymmetry induced at a prochiral centre of substrate either by the chirality of reagent or by one or more chiral centres presents in the substrate molecule itself. In an enantioselective reaction, asymmetric induction is equal to the enantiomeric excess (ee) and in diastereoselective reactions (giving rise to a new chiral centre), it is equal to diastereomeric excess (de).
3.1. Strategy of stereoselective synthesis
While synthesizing an optically active compound with multiple chiral centres (e.g., a natural product), one usually synthesizes the compound in racemic form fixing the relative configuration at all the chiral centres through diastereoselection and then applies the resolution technique.
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 3.1.1. Diastereoselective reactions
Diastereoselectivity
Cyclic system Acyclic system
Diastereoselectivity in acyclic system
Acyclic molecules are conformationally more mobile than cyclic. The first rationalizations of asymmetric induction were worked out for reactions in acyclic system. e.g., Cram’s rule and prelog’s rule. We separately discuss this subject topic in the forthcoming modules.
3.1.1.1. Addition of nucleophiles to carbonyls compound
Addition of nucleophiles such carbanions to carbonyls is one of most common method to generate a new C-C bond. Sato et al (1984) have achieved high diastereoselectivity in Grignard reactions and hydride addition with substrate (15) which do not contain a chelating group but have a bulky trimethylsilyl moiety as a part of L group. The syn compound (17) (Cram product) is obtained in over 99% yield. When it to the ketone (18) and the latter reduced with metal hydride, the anti diastereomer (20), again the Cram product, is obtained almost exclusively (Fig.
8).
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
Diastereoselective transformation of C=C bond 3.1.1.2. Addition of halogens to alkenes
The fact that the addition of halogens to alkenes is both stereoselective and stereospecific gives us additional information about the stereochemistry of the addition and the mechanism for the reaction (Fig.
9). When the bromination of cis-2-butene (3) gives (R,R) and (S,S)-2,3-dibromobutane (6) and bromination of trans-2-butene (2) gives meso-2,3-dibromobutane (5) (Fig. 10).
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
Is the addition of Br
2syn or anti? Let us take a deeper look into the
mechanism of addition:
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
Fig. 11: Addition of Br2 to alkenes and converting to Fisher projection
In determining whether a stereoselective addition is syn- or anti- you cannot simply look at the Fischer projection. Remember, it is often necessary to rotate about a carbon-carbon bond to get a molecule into the conformation that corresponds to the Fischer projection.
What does the stereochemistry tell us about the mechanism of addition of halogens of alkenes (Fig. 12)?
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 3.1.1.3. Hydroxylation of alkene: formation of vicinal diol
Hydroxylation of alkene is stereoselective as well as stereospecific. Several methods of hydroxylation of olefins are available giving 1,2-glycols. Oxidation with either osmium tetroxide (osmylation) or potassium permanganate or maleic acid furnishes a syn glycol (Fig.13).
Mechanism of hydroxylation with KMnO
4:
First addition of MnO4 in syn manner and gives the permanganate intermediate product.
Oxidation of trans alkene (2) with KMnO4 and gives (S,S)- & (R,R)-2,3-dihydroxybutane (23,
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
24) (Fig. 14.) and the oxidation of cis alkene (3) with KMnO4, gives meso-2,3-dihydroxybutane (25) ( Fig. 15).
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 3.1.1.4. Hydroxylation with HCO
2OH: formation of vicinal diol
Oxidation with HCO2OH gives the opposite product, means: Oxidation of cis-2-butene (3) with HCO2OH gives (S,S)- & (R,R)-2,3-dihydroxybutane (23,24) and oxidation of trans-2-butene (2) with HCO2OH gives meso-2,3-dihydroxybutane product (25) (Fig. 16).
Mechanism of Hydroxylation with HCO
2OH:
Alkene acts as a nucleophile and peracid act as an electrophile. First insertion of [O] takes place in the alkene which gives an epoxide (oxirane) intermediate followed by ring opening epoxide with water give an anti-glycol (Fig. 17). Same pathway followed with trans alkene.
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 3.1.1.5. Perhydroxylation:
Perhydroxylation of alkene (26) using iodine and a silver salt (Prevost reaction) similarly goes through a cyclic iodonium ion (27) followed by neighboring group participation (rough ‘a’) to give an anti-glycol (29) (Fig. 18). If the reaction carried out in the presence of moisture, the intermediate acylium ion (28) is directly hydrolyzed (route ‘b’) and gives a syn-glycol (30) (Woodward’ modification).
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 3.1.1.6. Hydroboration: (formation of an alcohol)
Hydroboration of an olefin takes place in a syn fashion with boron being attached to the less substituted carbon and the adduct on oxidative deboronation gives an alcohol. If the double bond is adjacent to a chiral centre, addition takes place to the less hindered distereotopic face with moderate to high distereoselection. Thus in the hydroboration of the terminal double bond in the ester (31) (Fig. 19), disiamyl borane reacts from the side anti to 4-Me giving 4,6-product (32) predominantly (87%) (Evans et al 1982).
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 3.1.1.2. Dehydrohalogenation of an alkyl halide via E
2mechanism:
E2 is stereoselective as well as stereospecific in nature. E2 is anti-elimination. The hydrogen and the halogen must be on opposite sides of the molecule (antiperiplanar) before the E2 elimination can take place. This makes sense as both the base and the leaving group is negatively charged.
Therefore they would try to be as far apart as possible. In addition, the leaving group is large and there is more routes for the removal of the adjacent proton if it is on the opposite side from the leaving group. e.g.-In the 1-bromo-1,2-diphenylpropane (33) goes through elimination of H
& Br in the presence of alc. KOH via E2 mechanism gives E & Z alkene (34, 35) (Fig. 20).
4 Stereoisomers 2 Stereoisomers (E)- & (Z)-
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
Mechanism of bimolecular elimination reaction (E2):-
3.1.1.2. Diastereoslection in cyclic systems:
Many natural products e.g. terpenes & steroids and alkaloids are cyclic compound with multiple chiral centres. There total syntheses and particularly those achieve during the last four decades &
illustrate the various strategies used in designing stereo selecting reaction in cyclic system.
3.1.1.2.1. Nucleophilic addition to cyclic ketones
The most extensive study has been made on the stereo chemistry of additions of nucleophiles specially hydrides, to cyclohexanones, cyclopentanones. And a few bicycle ketones. There are two possibilities: stereoselective formation of axial (more stable) alcohols. Considerable success has been had in both directions, especially in hydride reductions, which are discussed.
1. Formation of axial alcohols:
The secondary axial alcohols are generally less stable and therefore must be formed under kinetic control using bulky reagents which prefer to approach the carbonyl group from the less hindered equatorial side (steric approach control). A large number of reagents are now available which
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
gives the highly stereoselective products. The results of reduction of five substituted cyclohexanones with just three of such reagents are shown in Table 1.
Table 3.1. Stereoselective formation of axial alcohola
R-Substituted cyclohexanone
Li(s-Bu)3BHb (37)
Li (Siam)3BHc (38)
IsOB-OAlCl2d
(39)
4-t-Bu 96.5 99.0 92.0
4-Me 90.0 98.0 90.0
3-Me 94.5 99.0 92.0
2-Me 99.3 99.0 98.0
3,3,5-Me3 99.0 99.0 98.0
aFigure indicate percentage yields of axial alcohols under optimum condition. bBrown and Krishnamurthy (1972); cKrishnamurthy and Brown (1976). dEliel and Nasipuri (1965).
These are the structures of stereoselective Hydride transfer reagents.
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions 2. Formation of equatorial alcohols:
Maruaka et al 1985 and Nasipuri et al 1984 have developed method for the preparation of equatorial alcohols (45) from reduction of cyclohexanones (41) with t-butyl magnesium chloride (42) using methylalumino derivative of bis-(2, 6-di-t-butyl-4-methylphenoxide) (43) (Fig. 21a) and reduction with fluorenyloxyaluminium dichloride (44) (Fig. 21b).
3.1.1.2.2. Reduction of 1-(R)-camphor:-
Reduction of 1-(R)-camphor (46) by one quuivalent of lithium aluminium hydride afforded a 90.2:9.8 mixture of isobonenol (47) with bornenol (48), an 88.7:11.3 ratio was obtained with racemic camphor under identical reaction conditions (Fig. 22).
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry
Module No. 24: Stereoselective and Stereospecific Reactions
A category of diastereoselective processes involves the coupling of two compounds at prostereogenic centres with the formation of two new stereocenters as may occur with the aldol and Michael reactions.
The focus of concern here is with the stereochemical relationship between these centres (i.e., simple stereoselectivity).
4. Summary
In summary of this module, we have described the overview of stereoselective synthesis with ample amount of illustrations to make it readily understood.
Stereoselectivity has been classified under two categories enantioselectivity and diastereoselectivity.
Stereospecific reactions, are reactions in which stereo chemically different molecules react in different way. In this case the cis- and trans- stereoisomers give different products.
Stereoselective reaction, are reactions that yield predominantly one stereoisomer (or one pair of enantiomers) of several diastereomers.
We have discussed the diastereoselection in acyclic system with C-C and C=C bond and we have also discussed diastereoselection in cyclic compounds mainly on the basis of axial and equatorial position of a substituent and has been illustrated by reaction such as nucleophilic addition to cyclohexanones, and other suitable substrate.
