The document discusses chirality in heteroatom systems where chirality arises from a non-carbon centre. It explains that compounds containing nitrogen, phosphorus, sulfur or other atoms can exhibit stereochemistry when the atom forms a tetrahedral structure with four different groups. The stereochemistry of these compounds provides useful information for drug applications. It then focuses on the specific stereochemistry of various nitrogen, phosphorus and sulfur compounds, including amines, oximes, azo compounds, phosphines and sulfoxides. It describes how these compounds can exhibit geometrical isomers, inversion barriers, and retention or inversion of configuration under chemical reactions.

1. DOS&R IN ORGANIC CHEMISTRY
TUMKUR UNIVERSITY
Chirality in
Heteroatom Systems
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2. where chirality is due to the presence of a noncarbon
Centre?
• 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.
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4. 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.
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. On the other hand, most of the quaternary
ammonium ions with no non-bonded electrons and possessing
four bonds to nitrogen do not invert.
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6. 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 , 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 which exists in its optically active form (levo).
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 in cis form. Substitution on N by
halogen increases the barrier to N-inversion. Thus, 1-fluoro-2,2-
bis(trifluoromethyl)aziridine does not invert even at 190oC and exists in
its most stable conformation.
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7. • In six membered heterocycles ring inversion and pyramidal inversion
go side by side and are competitive. In 1,3-dimethylpiperidine 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
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8. 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 in solution.
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 . 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 .
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9. • 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 .
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.
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10. 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.
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11. • 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.
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.
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13. • 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.
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14. 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.
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
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15. 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.
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.
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16. 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.
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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

18.  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.
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19.  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.
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