Subject Chemistry Paper No and Title 1 and Organic Chemistry-I (Nature of bonding and Stereochemistry) Module No and 35 and Stereochemistry of the compounds Title containing Nitrogen, Sulphur and Phosphorus Module Tag CHE_P1_M35_e-text CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Stereochemistry of Nitrogen 4. Stereochemistry of Phosphorus 5. Stereochemistry of Sulphur 6. Summary CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus 1. Learning Outcomes After studying this module, you shall be able to Understand the stereochemistry of compounds containing nitrogen, phosphorous or sulphur either alone or in combination. Explain the effect of lone pair on stereochemistry. 2. Introduction Any compound containing atom like carbon, nitrogen, phosphorus and sulphur forms a tetrahedral structure with four groups attached to them. When their four groups are different, they exhibit stereochemical behaviour. Stereochemistry of compounds containing nitrogen, sulphur and phosphorous gives very interesting and useful information’s about their applications in drugs and medicines. This has been proved in various fields that the compound in different stereochemical form behaves in different manner. For example, the R isomer of thalidomide is an effective drug to treat morning sickness in pregnant women where as its S isomer causes deformities in embryos. In another example, the interaction of propafenone with respect to 5-hydroxylation is stereoselective in nature. It has been studied and found that the R-propafenone is more potent inhibitor than it’s S-enantiomer with respect to cytochrome P450IID6-mediated 5- hydroxylation. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus 3. Stereochemistry of Nitrogen compounds Nitrogen is tetracoordinate in ammonium salts and tricoordinate in amines and exhibits chirality with this coordination in organic compounds. Substituted quaternary ammonium compounds (I) and N-oxides (II) are examples of tetracoordinate chiral center. 3.1 Amines Tricoordinate amine can be treated in same manner as tetracoordinate compounds with lone pair as the fourth substituent. A nitrogen atom in chiral amines has a pair of non- bonded electrons that turns inside out even at room temperature and hence undergoes fast amine inversion. Amine inversion is an example of conformational isomers, which is also called invertomers. Chiral amines cannot be resolved due to amine inversion (Figure 1). On the other hand, most of the quaternary ammonium ions with no non-bonded electrons and possessing four bonds to nitrogen do not invert. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus Figure 1 Inversion of amines can be restricted when a nitrogen atom forms part of a ring. This leads to increase in barrier to inversion. For example, in Troger’s base (IV), nitrogen is placed on bridgehead and inversion cannot take place without breaking a bond. Therefore, stable enantiomers are formed which can be separated easily. Another example is 2-methyl-3,3-diphenyloxaziridine (V) which exists in its optically active form (levo). CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus For the substituted aziridines, the invertomer which has the R group anti to the ring substituent is more stable. The enantiomers of amine are termed as invertomers. 2-1’- napthylaziridines (VI) exists in the anti conformation and 2,3-diphenylaziridine (VII) in cis form. Substitution on N by halogen increases the barrier to N-inversion. Thus, 1- fluoro-2,2-bis(trifluoromethyl)aziridine (VIII) does not invert even at 190oC and exists in its most stable conformation. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus In six membered heterocycles ring inversion and pyramidal inversion go side by side and are competitive. In 1,3-dimethylpiperidine (Figure 2), ring inversion (RI) leads to conformational isomers and the configurational isomers (cis and trans) remain as it is. But in pyramidal inversion (PI), cis isomer is converted into trans isomer and vice versa. Figure 2 3.2 Oximes The oximes are formed by the reaction of carbonyl compounds with hydroxyl amines. They are chemical compounds with general formula R1R2C=NOH. It can exist in tautomeric forms (X) and (XI) in solution with equilibrium lying towards (X). CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus Based on the substitution at ‘R’, the oximes are of two types: (a) Aldoximes: These are derived from aldehydes and possess R = H. (b) Ketoximes: These are derived from ketones and possess R = alkyl or aryl groups. The oximes show geometrical isomerism due to restricted rotation of C=N bond. The terms syn and anti are used for oximes instead of cis and trans. In case of aldoximes, the syn form is the one in which both the hydrogen and the hydroxyl (-OH) group are on the same side of the C=N bond (XIV). The anti form is the one in which both the hydrogen and the hydroxyl (-OH) group are on the opposite side of the C=N bond (XIV). CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus In case of ketoximes, the syn and anti forms are based on the spatial relationship between the first group given in the name and the hydroxyl group (-OH). For example, the ketoxime of 2-butanone can be named as either syn methyl ethyl ketoxime or anti ethyl methyl ketoxime (XV). CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus E-Z notation of oximes: The E-Z notations are better in differentiating the geometrical isomers of oximes. The Z oximes have hydroxyl group and the group with higher priority on the same side of C=N bond. However in the E oxime, they are arranged on the opposite sides of the C=N bond. For example, the syn acetaldoxime is named as (E)-acetaldoxime (or 1E-N- hydroxyethanimine), since the hydroxy group and the group with higher priority i.e., methyl group are on the different sides of the C=N bond. On the other hand, the anti acetaldoxime is named as (Z)-acetaldoxime (or 1Z-N-hydroxyethanimine), since the hydroxy group and the group with higher priority i.e., methyl group are on the same sides of the C=N bond. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus 3.3 Nitrogen compounds containing double bond (azo compounds) The azo compounds are an important class of compounds and this account for 60-70% of all dyes. Geometrical isomerism are possible in the compounds containing nitrogen – nitrogen double bond (-N=N-) and plays its role in their properties. The cis and trans isomerism in these compounds are usually designated as syn and anti respectively. The change from trans (anti) which is a preferred isomeric form to cis (syn) can be effected by exposure to UV radiation. Selected examples of nitrogen compounds containing double bond includes diazosulphonates (XV), diazocyanides (XVI), azobenzene (XVII), azoxybenzene (XVIII), o-nitroacetophenone azine (XIX). CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus The E/Z notifications have also been used for these compounds. This is based on the presence of two highest priority atoms or groups on same side or opposite side. When the atom/groups are on opposite side, symbol ‘E’ is used and when they are on the same side, ‘Z’ is used. For example, azobenzene exists as E-azobenzene and Z-azobenzene. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus 3.4 Fused bicyclic systems containing nitrogen in ring Quinolizidine (XX) and decahydroquinoline (XXI) are two important fused bicyclic systems containing N atom in the ring. Quinolizidine is achiral and exists in cis and trans form. The trans form (XXa) converts into cis form (XXb) or its mirror image (XXb’). The three conformers are in dynamic equilibrium. The cis form is less stable than trans form by 18.5-20.0 kJ mol -1. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus Decahydroquinoline exists in cis and trans form. Pyramidal inversion at N in trans form gives rise to invertomers (XXIa) and (XXIb). Here, N-He (He means hydrogen atom present at equitorial position) is preferred. In cis form the two conformers are obtained by ring inversion. 4. Stereochemistry of Phosphorus compounds Like nitrogen, phosphorous with symbol ‘P’ is in the same group of the periodic table. It also forms tricoodinate and tetracoordinate compounds having stereochemical behaviour. The stereochemistry of phosphorous compounds started in 1950s. Some of the biological transformations are also studies with 4-coordinate phosphorous derivatives. Phosphonium compounds (I), phosphine oxides (II) and phosphines (III) have phosphorus as chiral center when all the substituents are different. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No.