50 Stercochem8ry

(i) and (ii)_simuttaneously: either the longest carbon chain can be placed vertically
as in XVIII or the hrghest oxidised end, carboxylic group be placed- at the
op.
.For amino acids, L(-)-serine with the configuration (XIX) is used as reference
which introduces a further complication in delining the configuration of a
molecule containing both hydroxyl and amino groups. Thus 1-almino_24t-
oxymannonic_acid (XX) may be given D lab€l with reference to glyceraldehyde
(see C-5) but L label wirh ref€rence to serine (see C-2). The problern=can
be solved
by using subscripts g' for glyceraldehyde and .s, for serine so that the amino-
mannonic scid may be designated either as Dc or as L (Slocum, Sugarman, and
Tucker l97l).

4,3.2 Rand S Nomenclature

A self-consistent and unambiguous system of configurational nomenclature based

on the threedimensional structures of molecules was first introduced by Cahn and
Ingo_ld (1951) 4nd suhrsequently elaborated by Cahn, Ingold, and pr;log (1955,
1965). The system is known as CIp nomenclatue after the names of the authors.
{yrdinq to this system, the conliguration of a moldcule is specified uniquely
either as R (from rectus, Latin for right) or as .S (from srhryer, Latin for left) whicir
is independent of nomenclature and numbering. Like D and L, R and S are also
to-pographical descriptors, used as prelixes* and have nothing to do with the signs
of rotation.
Assrgnment of configuration is done by the application of two rules: the
sequence rule (consisting ot several standard sutrules) and the chirality
rule. The
sequence rule arrauges the four ligands of a ihiral centre (Cabcd) in a priority
s€quetrce,_e.g.,a>blcld(.a,havingthehighestpriorityand.d'th€lowest),or
the ligands may be numbered: 1) 2) 3) 4. The chirai centre is then viewed
from the side remoie from the lowest ranking group (.d' or 4) (Figure 4.d). If from

o
.--'J d-(. c*.8
"{-o .

{. v

.+,
o o
lt ,
llA
llrI bti,<c
d d

Ftgur€ 4.6 Chirality rule: .R and S romenclaturc

*8 8trd S are usually put within par€ h€sis but trot nec€ssarily, as in this text.
 Stereoisomeism and Centre of Chirality 5l
tbis point of uew. the arrangement a-b*c (or l*2*3)
appears in the
clockwise (right-handed) direction, the configuration is R atrd if the aratrgement
appears in the anliclockwise (left-handed) direction, the configwation is S. This is
known as the chirality rule.
The standard subrules which determine the priority order are six in number
(actually, they themselves may be called the sequence rules) and have been stated
under the headings (0)-(5) (Cahn, Ingold, and Prelog 1956)+. They must be
applied in succesion, i.e., one after the other in the order stated.

Sequence mlcs or standard subrubs

(0) Nearer end ofan axis or a plane Drecedes the farther end (proximity rule).
(l) Higher atomic number preredes lower, e.g., S F ) )
O > N> C > H.
(2) Higher atomic mass number precedes,lower. e.g., T > D > H.
(3) Cis precedes tran$ and Z precedes ET
(4) Like pair RR or S,S precedes unlike pair R,S or S,R; M,M or P,P
precedes MP or P,M; R,M or S,P precedes RP or S,M; M,R ol P,S
precedeo MS or P,R; and r precedes
^s.
(5) .R precedes ,S: and M precedes P.
For the majonty or compounds, only subrules (1) and (2) are importanli the
other subrul€s apply only to special cases. Subrule (0) is applicable to axial land
planar chirality to be discussed in Chapter 5. Subrule (1) needs further elaboraition
which is done in the following paragraphs:
- L Atoms direcUy attached to the central chiral atom must be sequencedll5rst
according to subrule (l). If the priority still remains,undecided for so_lEe=of-the
ligands, one passes over to the next atom h
the ligands and the exploration
continues until a d€cision is reached on the basis of the subrules. The following
examples illustrate the point :

-CIl2Cx\ > -CHli -CH, OII> -CHzM{:; {H:CHFBT) {H:CHFC/

(Decision is reached at the italicised atoms)

It may be noted that subrule (2) must not be used until subnrle (l) is completely
exhausted; thus -CHTCHTCE > -CDTCIL because propyl ) ethyl (subrule l);
but -CHzCDzCIIT ) -CIIzCI{zCHr (subnrle 2).
2. In case a ligand bifurcates, one must prd,ceed along the brancb providing the
highest precedence until a difference is encountered. The decision must be made at
the e/Abs, opportunity and once made, cannot be changed from consideration of
subBtituents farther along the chain. These poins are illustrated below:
cH" cH.
-CH2 CHCH2CI > -CH2CHCH2CH3; -CH2CC
i"l" > -CH2CCH2ofl
3
tt-t-l
cHs cHa cH3 H

tPrelog
and tlelmchen (1982) have proposod a few revisioos and modificstions of th€ rubrul€s which
are mostly urinor i! nature. For sofle recent suggestions, se€ Dodziuk end Mirowicz (1990).
isome of lhe Ermi[otoSies stch as Z E, M, E r, afr s .re discussed late..

- Jr',lo
,
i{? u*a.
t') '
 52 Stereochemislrl

J. When the central atom is a part of a ring system, each branch is followed
until a decision is reached as shown in Figure 4.7a below (see Prelog and
Helmchen 1982 for complicated cases):
-CH-O
I
f, -?r-?
" ,:).';;:1,. b. -cH-o""
ll (o) (c)
-cH.
\cH
oH cH,

!
Flgur€ 47 (a) Priority sequence in ring syst€m; (b) aldehyd€ v€Eus hydrated aldehyde
versus hemiaceal

4. In the cas€ of atoms with multiple linkages, the atom to which they are
multiply bonded must b€ duplicated or triPlicated as the case may be at both ends
I of thi multiple bond. The duplicate atoms are put ilto parenthests and except for
hydrogen are made up (complemented) to ligancy four with phantom atoms of
oLmii numbet zero. Thus the representation of the aldehyde group, -CHO is
ihown (Figurc 4.7b) along with its hydrated form and hemiacetal for comparison'
From the structures (A), (B), and (C), it is clear that -CHO has preference over
the hydrat€d form (B) but the hemiacetal (C) has preference over the aldehyd€
(A). iAe hst point illustrates the utility of the phantom atom wtich has lower
priority than hydrogen. In the following illustrations, (Figure 4.8) the phantom
atoms are omitted.
oH otl oH

ii-to*
(o)(c)
-l H FHs

'll (c) (c)

\cx.

(?) (?) 9Hc

-C=CH --' -c-c-H -t-c'r,
t-
,1,,1, bHs

(N) (C)
/u;
-l-^l - t""a
-CHc-N.
,[, ,1,

ii ,.,-isi., cH2-cH2\
-c[r iH2
\cnr-cx/ or
i'a
-c-cH3
iru
Ai (ctH(i)H
Ftgure 4.E Priority sequence of some common groupc
 Stereoisomeism and Centre of Chirality 53

In Table 4. I , a few atoms and groups are listed in order of increasing priority. In
the absence of a lone pair of electrons (in the case of tricoordinate atoms), H has
the lowest priority. Actually, a lone pair (as on N) is equated to a phantom atom
of atomic number zero.
Table 4.1 Atoms a[d groups with increaslng priority

l.H 10. CH = CH: 19. cqR 28. OCOR

2.D ll. c(cHrr 20. NII 29. F
3. CH1 12. c= cH 21. NHCHI 30. sH
4. CH,CHT 13. GHs 22. N(CH:)z 3r. sR
5. CH,(CE,)ICH: 14. cH,oH 23. NO 32. SOR
6. CHz - CH = CHr 15. CH=O 24. NO 33. SO,R
7. CH?-C=CH 16. coR 23. OH 34. Cl
8. CH,C6H5 t7. coNH? 26. OCHI 35. Er
9. CH(CH3)' 18. cqH ' 27. OGH5 36. I

Once the priority order of the ligands is settl€d, the configurational assignment is
made by appllng the chirality rule. If one deals with a thr€cdimensional model,
the task is very simple; one only has to look at the molecule from the side opposite
to 'd' and determine the order of a b c. Dif6culty arises since most of the
- -
molecules are repres€nted by Fischer projection. The method recommended earlier
by Eliel (1952) was to draw the projection always with 'd' at, the bottom as shown
in Figure 4.6 (bottom row) and then describe a semicircle joining a b c the * -
direction of, hich indicates the configuration. Aly Fischer prgection csn be
manipulet€d either by exchanging two pairs of ligands or rotating a group of thre€
either clockwise or anticlockwise to conform to this requirement. This is demons-
trated in assigning the configurational descriptors to D-(*lglyceraldehyde and
L(-)-serine respectively (Figure 4.9). In both the instances, R and S correspond
to D and L respebtively but this do€s oot mean that the two pairs of descriptors 8re
necessarily synonymous (e.g., I-cysteine =.rR-clnteine)t.

cHo cHo,-, 9ooH,-. coaH

Hdox :
(r' i,., tt' H2N{}H
'5rro, Ho-.6{'JroH - HocHz4t'N;i
Exrox (!r i,., t"
(xvil) (xrx)
Flgure 4.9 Assigoment ofn snd S d€scaipton

A number of altemative procedures for asigning R and S on the basis of

Fischer projection have been suggested from time to time. The simplest ond moot
is
widely accepted one due io Ephng (1982). The procrdure, named as "very
good' (a mnemonic device for "n"t1;"61: good") conslqt! of two operations :
fi*rng up the priority order of the ligands and tracing a semicircle joining
0 .- b - c ignoring 'd', the lowest priority 8roup. If 'd' is on the verticsl line in

*lo cysbioe, CHZOH of seriae is rcplaced by CHTSII haviog higher priority over CO2H whici
accourts tor the charg€ of clP nomenclaturc,
54 Stereochemi*ry

Fischer projection (it does not matter whether it is at the top or at th€ bo$om), the
sequence gives the correct descriptor*; if on the other hand, t'
is on the horizontal
line, the sequence giv€s the wrong answer and the descriptor assiSled on this basis
.should be reversed.'fhe procedure is illustrated with (+)-tartaric acid (XXD'
D-(-Farabinose (XXII), and 3-bromobutan-2-ol (XX[D (Figure 4.10). In the
nrst two cases, H rs on the horizontal line in all the chiral centres and so the
descripton arrived at from the sequence I -* b - c have to be reversed' In the third
case, H is on the vertical line in both the chiral centres and the sequenc€ a * b - c
gives the correct descriptor.

cHo
co^H
/'1", c
Hortln H
I

H+c-r-oH
\r2
H{NoH HO-\g{-CH3
\,
Ho=clH H_(cioH cH.Jt!er
Y3 cH2oH
co2 H H

(xxt) (xxil) (xxilt)

2@),3\R) z(9l ,3tRl,4@l 2(s),3 (.r)
Figure 4.10 Exrmples of the 'very good' mnemonic

Cyclic molecules such as sieroids and terp€nes are usually projected on the plane
of the paper and hydrogens (or subotituenti) located below and above the plane
are assigned c and B descriptors respectively ( o represented by dotted and B by
thick lines as shown in 3<holestbnol XXIV in Figue 4. I I )-a system re-
comoended by the Chemical Abstract Service (Pure and Applied Chem', 1972,
31,283). These descriptors relat€ to relative configuration and are meaningful if
the cyclrc system is drawn in an accepted way as in sterords and terpenes. For
absolute configuration, each of the chiral centre in the cyclic molecule must be
defrned by R,S descriptors following CIP nomenclature. A conveni*nt method has
been suggested by Eliel (1985) which is as follows. At any particular chiral centre,
one ligand must be clearly in the front (F) or clearly in the back (B). This would
be regarded as the reference ligand. The order (clockwise or anticlockwise) of the
remaiaing three can be very easily determined, all three being in the plane of the
paper. If this reference ligand is 4/B (lowest locant and in the back), the sequence
;f-Oe remsidng three ligands would give the corr€ct descriptor. So 4/B(+) may
be used as a mnemoniC (+) stads for conectl. For other ombinations' the
numben will altemate v/ith sigrrs, e.g., 4/B (+), 3/B(-), 2/B(+), l/B(-) and
4/F(-\, 3/F(+),2/F(-), l/F(+). For example, the C-10 chiral centre of
cholestanol (XXy) conesponds to 4/F and so although the order I
.- 2 - 3 is

'The 66thod is sioply ao €xteDsiotr of Eliel's since a Fischer projection N perBitt€d l8f rotation and
it is immatorid whether d is put at the bottom or at tte top of the projectiod.