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. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus
Phosphines like amines exist in trigonal pyramidal structural form. Tertiary phosphines cannot be resolved easily due to inversion similar to the tertiary amines. However, inversion in phosphines is slower than in amines. It can be brought to zero by increasing the weight of substituted groups. For example, on replacing three hydrogen atoms by deuterium atoms changes the frequency of inversion to 6×103 as compared to 5×106. The optically active phosphonium salt and phosphines acts as precursor for the synthesis of optically active phosphines. Phosphines on treatment with hydrogen peroxide get converted to phosphine oxide with retention of configuration. For example, (S)-(+)- Methylphenylpropylphosphine reacts with hydrogen peroxide to get (S)-(+)- Methylphenylpropylphosphine oxide (Scheme 1). This process is useful in the preparation of phosphine oxide with absolute configuration.
Scheme 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
The tetracoordinate pentavalent phosphorous esters undergoes nucleophilic displacement reactions at phosphorous in highly stereoselective way leading to complete inversion or retention of configuration. These possibilities are dependent on function of the nucleophile, leaving group and the reaction conditions. Phosphorous sulphides are another group of compound studied widely for stereochemistry.
5. Stereochemistry of Sulphur compounds
Chiral sulphur compounds play important role as catalyst and/or reagents in asymmetric synthesis. The sulphur compounds possess higher pyramidal inversion barriers than amines. Also, this has been observed that the chiral phosphines and sulphonium salts are stable at room temperature with respect to their configuration whereas the acyclic amines racemize easily. Hexavalent sulphur compounds (I), sulphonium salts (II) and sulphoxides (III) consists sulphur as chiral center, depending upon the groups attached. In all the cases, the sulphur is attached with different atoms or groups. However, the sulphones (IV) which also possess sulphur bonds tetrahedrally, do not display chirality due to the presence of two oxygen atoms on sulphur. But, if sulphones contain different isotopes of oxygen like O16 and O18 (IV), they show chirality. Stability of pyramidal configuration chirality increases with increase in atomic number. Therefore, inversion in sulphur compounds is slow.
CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus
Structure (IV) is illustration of chirality due to two alkyl groups differing only in isotopes of carbon ie 12C versus 13C.
Cyclic 1,4-dithiane (V) exists in two geometrical isomers and ring exists in chair form. In trans form S=O is trans and at axial position. CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus
Anomeric effect in dithiane Sulphur containing compounds show anomeric effect where polar groups bonded to C-1 (the anomeric carbon of a glycopyranosyl derivative) have a thermodynamic preference to occupy an axial position rather than equatorial position. For example, trans- 2, 3- dichloro-1, 4-dithiane (VI) exists in diaxial conformation due to greater relaxation of 1,3- diaxial interactions
Tetravalent phosphorus groups prefer axial position in 1, 3-dithiane (VII) and 1, 3, 5- trithianes (VIII).
CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus
Cyclic sulfoxides on alkylation results in trans stereochemistry between the sulfoxide oxygen atom and new alkyl group as the oxidation proceeds faster from the exo face. Alkylation trans to the exo oxygen gave the desired endo product (IX).
CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus
6. Summary
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. Tricoordinate amine can be treated in same manner as tetracoordinate compounds with lone pair as the fourth substituent. Chiral amines cannot be resolved due to amine inversion. Most of the quaternary ammonium ions with no non-bonded electrons and possessing four bonds to nitrogen do not invert. The oximes are chemical compounds with general formula R1R2C=NOH. It can exist in geometrical isomeric form as cis/trans or syn/anti or E/Z. The azo compounds also show geometrical isomerism. The cis and trans isomerism in azo 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. Phosphorous compounds also form tricoodinate and tetracoordinate compounds having stereochemical behaviour. Hexavalent sulphur compounds (I), sulphonium salts (II) and sulphoxides (III) consists sulphur as chiral center, depending upon the groups attached.
CHEMISTRY PAPER No. 1: Organic Chemistry-I (Nature of bonding and Stereochemistry) MODULE No. 35: Stereochemistry of the compounds containing Nitrogen, Sulphur and Phosphorus