R. S. ~ a h n ' The Chemical Society
London, England
I
I
An Introduction to the Sequence Rule A system for the specification of absolute configuration
The "sequence rulen is an essential part of a procedure that describes, in simple symbols, the absolute configuration of the various types of optically active compound. It has been elaborated by Professor Sir Christopher Ingold, Professor V. Prelog, and the present writer during the last 12 years in three papers (1-S), of which the second and the third amend, consolidate, and extend the one preceding it. Configuration has been specified very satisfactorily in limited fields by other methods. By international agreement D and L are nsed for amino acids and carbohydrates, and cr and j3 for steroid rings A-E. At first these applied only to configurations relative to serine for amino acids, glyceraldehyde for carbohydrates, and the 19-methyl group for steroids; but luckily they remained unchanged when the absolute configurations became known, i.e., when the actual positions of the atoms in space were found. However, these D and L, or and 6, symbols cannot be nsed, as defined for these fields, as a general system for all chemistry. It would depend on conventions for converting one compound into another; in many cases there just is no generally accepted convention for such a conversion; in some cases none can he easily made; in others conventions can he made in various ways that lead to different symbols. A general solution has to he independent of interconversion of two compounds. The sequence rule is one such independent method, being applied to the model of the single substance in question; it is coming increasingly into use, and its elementary features have been described in some modern texts (4-6); but the detail that these texts can give is inadequate for many of the situations that a chemist meets, and on the other hand the three original papers are too detailed except for the specialist. It is hoped that the present paper may fill the gap. Structural features that can lead to optical activity are of rather varied type, and the full development of the sequence rule takes account of all of them. Complex situations can arise, but they do so in practice in only a very small proportion of actual cases, and in the others the sequence rule offers no difficulty. The present paper describes the relatively simple methods that suffice for by far the majority of optically active organic compounds, namely, those containing asymmetric carbon atoms [or other tetrahedral center such as nitrogen(1V) or tin(IV)]. I n addition, because of their importance, this paper will deal with hindered biaryls and geometrically analogous cases
' Burlington House, Piccadilly, London, W.I., England. Reprints of this paper may be obtained from Chemical Abstracts Service, Ohio State University, Columbus, Ohio; price 50 cents. 116
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Journal of Chemical Education
such as the allenes. A brief final section lists the further, more complex extensions that are treated in the two later papers. During their development some of the earlier sequence-rule procedures were amended: in the account that followshere, the amendments are consolidated into the form which now appears to be stable. Asymmetry and Chirality
The essential condition for optical activity is that a molecule shall not be identical with its mirror image. It has been customary to refer to this condition as asymmetry; hut that term is not strictly correct since some molecules exist which are not identical with their mirror images but yet possess symmetry in virtue of axes of rotation. To describe models which have no symmetry or a t most axes of rotation, the adjective "chiral" is reintroduced in the third sequence-rule paper (5); "chirality" expresses the necessary and sufficient condition for the existence of enantiomers. The word "chiral" means "of or pertaining to the hand"; "chirality" means "handedness" and was nsed in that sense by Kelvin (7) in 1884. We may note that a grouping Cahcd has no symmetry whatsoever, so that the term "asymmetric carbon atom" is entirely correct provided that, as is always the case, it is understood t o include the surroundings of that one atom. The above vocabulary will be used in the description that follows. The Chiral Center
The commonest cause of optical activity is the existence of one or more chiral centers, which in organic chemistry are usually asymmetric carbon atoms. For carbon and other atoms to which four ligands are attached this requires that the ligands shall be all different; we can express this in a symbol Cabcd, and the space model for this may be depicted as 1. We suppose that the groups a, h, c, d are arranged in some way in
that order; we shall describe below the sequence rule by means of which that is done, but for the present we need to know only that the order is a > b > c> d.= If the model (1) is viewed from the side remote from the fourth member d, then proceeding from a to b to c
dextrorotation (Latin, dexter = right); in sequence-rule language the adjective rectus (Latin, rectus = right) and the symbol R are used. Now, if we interchange the positions of any two groups, we convert the tetrahedral model into its mirror image; in (2) this has been done by interchanging b and c. When model (2) is viewed as before, passing from a to b to c traces an anti-clockwise course; in sequence-rule language this is called sinister (Latin, sinister = left) and given the symhol 8. If the molecule contains more than one chiral center, this procedure is applied to each, and the stereochemistry is expressed as a multiplicity of R, S symbols. I n the names of actual compounds, the symbols R and S are written in parentheses and followed by a hyphen, in front of the complete name of the compound [cf. ( 2 ) Examples are (R)-glyceraldehyde, (R,R)-tartaric acid (dextrorotatory), (R,S)tartaric acid (meso), (2S,3S)-threonine. Racemates are designated by a prefix RAY)-,^ e.g., (RS)-glyceraldehyde, (RS,RS)-tartaric acid (racemic). It will he apparent that a fundamental feature of sequence-rule procedure is that a three-dimensional model is, and must always he, considered. Projections must he handled, not as the two-dimensional picture that they present, but as the representations of a threedimensional model that they actually are, and the rest of this section will he devoted t o showing some ways in which this can he done. There is no difficulty in assigning R, S symbols if a model is available that can he turned for viewing in the appropriate direction. However, an ordinary structural formula does not always present the stereochemistry so lucidly, and those not accustomed to thinking in three dimensions may need a little practice. Direct translation of ordinary structural formulas into three-dimensional ones may give pictures such as 3a-d,
The customary Fischer projection is not difficult to handle. The Fischer projection (5a) can be translated into its equivalent (5b) or (5c),both of which show clearly the R-configuration of this model. Alternatively, a method n.hich does not need three-dimensional thinking
a t all is as follows: If group d is a t the bottom, as in (6), one merely reads the direction of rotation a-h-c; in (6) it is anticlockwise, so the configuration of (6) is S. If d is not a t the bottom, interchange it with the group that is a t the bottom. For instance, with (5a), interchange b and d, giving (6), and then read the direction a-h-c as before, which gives S; hut now the single interchange, from whatever position it was made, will have reversed the configuration so that the rotation read off will be the opposite of that of the original. Thus, for (5a) the interchange gave (6), which is an S-form, so that the original (5a) had the R-configuration, as established also above by other methods.& COOH
I
COOH !
all of which are views of the same R-form. When constructing these it is useful to remember that not more than two bonds may be placed in the plane of the paper and that a third must proceed behind, and the fourth in front of, that plane. Sometimes, when two asymmetric carbon atoms are directly linked, it may avoid confusion to use wedge bonds, to the exclusion of dotted lines, as in (4). If the fourth group d lies in front of the plane of the paper, as it does in (3c) and ( 3 4 , the procedure requires that the model he viewed from behind the plane of the paper. The direction of rotation, seen from the hack, is, of course, the opposite of what it appears to he when viewed from the front.
A word of warning may be here interpolated. The Fischer projection requires orientation of a model from top to bottom, as in (7a). Amino acids are often written "sideways," by merely turning the Fischer projection on its side, as in (7b); it must then be remembered that the three-dimensional picture is also turned sideways, so that in (7b) it is the vertical bonds that are above the plane of the paper and not, as in (7a), the horizontal ones. Before leaving the tetrahedral model we may note one further use of it. Sometimes, the molecular structure fixes the orientation of a tervalent atom and that atom m y then he a chiral center. For instance, in a-sparteine (8) this occurs with both nitrogen atoms.
This manner of incorporating the symbol in a name is purely conventional. For consistency it should he followed in a normal text, but no difficulty is likely if, for linguistic reasons or in indexes, R and S are written at the end of a name or without parentheses.
Alternatively, one may interchange two pairs of groups, still so as to place the group d at the bottom, and then the direction of rotation ~rb-cgives the sequence-rule symhol of the original model without reversal. Actually, hy either method, group d may he placed either at the bottom or at the top; but the simpler instruction may be easier to remember. Volume 41, Number 3, Morch 1964
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117
The rules described in the next section fix the order a, h, c marked in formula (8); we now need a fourth
we have still to decide between CHI and CH,OH; in substance (12), H is d but we still have to decide among the other three groups. The further decisions are taken by working outward concurrently along the groups still in question, atom by atom, up t o the first point of H /
/
difference. For compound (11) we have -C-H and \ H / H -C-OH; the oxygen atom here is decisive; so group. To obtain this we visualize the lone pair of electrons on the nitrogen atom as a phantom atom; since direction attaches t o this lone pair the steric situation a t the left-hand nitrogen atom is correctly represented as @a),with the phantom shown by o; and since this is a phantom, it is ascribed atomic number zero which, as will be shown, always places it last in the sequence, i.e., as d. Thus the nitrogen atoms may be described as a n R-center. Lastly, it should he mentioned that this approach to the chiral center was followed independently by Terentiev and Potapov (S), but with Greek symbols p and u in place of R and Sand with different illustrations. However, the two systems differ fundamentally in the way in which priority is assigned to the groups a, b, c, d, and the systems are not interchangeable. The sequence-rule procedure for assigning these priorities is described in the next section.
\
H CH,-OH has priority over CH2-H; and the complete sequence is C1 > CHzOH > H, which gives an R-form. For substance (12) we similarly have the sequence CHz-C1> C H r O H > CHa > H, and this compouud is. also a n R-form. To reach a decision with substance (13) we must go one step further; here we have a t once H = d ; then the two -CH2-C groups have priority over CH3, so CH3 = c; and finally - C H y C H y O has priority
The Sequence Rule
The Principle. The sequence rule itself is the method by which the groups a, h, c, d are arranged in sequence so that stereochemical symbols R or S may be alloted. Four suh-rules are needed, but the last three are needed only in rare, special cases and we shall in this paper mention only the first two. Sub-rule 1 is: Higher atomic number precedes lower. Suppose we have a compound (9) ; the atomic numbers of the atoms Br, Cl, C, H attached to the central carbon atom obviously arrange themselves in that order by sub-rule 1, giving the model shown which is then clearly a n R-form. Sub-rule 9 is: Higher mass number precedes lower. Suppose we have a molecule (lo), the mass numbers arrange the atoms C1, C, D, H in that order, giving also an R-symbol.
Saturated Chains and Rings. More often than not, in organic chemical practice, two or more atoms directly attached to the chiral center are identical. I n that case, as a first step, priorities are assigned as far as possible. For instance, in ( l l ) , Cl is a, and H i s d, hut
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Journol of Chemical Education
over CH-CH-H; so that the sequence a, b, c, d is as shown and again this is an R-form. Analogously, for substance (14) the sequence is -CHC2 >-CH2C > CH3> H, illustrating how secondary always have priority over primary alkyl groups; and tertiary similarly have priority over secondary ones. A few variations need to be considered also. I n compound (15) we have to decide between two groups both 0
/
starting with -CH. \
The rule is that a t the
'c
branch point we proceed first along the prior branch,. here along the oxygen branch; we obtain in (15)
-C(CH)-0-H on the left and -C(CH)-0-C on the right, the latter having priority. Only if the prior branches do not differ do we proceed along the other(s); for instance, in (16) the two oxygen branches are the same and we then have to revert t o the second branch, finding -C(O,H)-CHC2 > -C(OH)-CH2C.
This procedure a t branch points applies, of course, equally, to all-carbon chains. I n (17) the secondary-carbon chains (the lower ones) are followed first and the oxygen atom of -C(C,H)-CH2-0 on the right-hand side provides the priority. I n (18) the two secondary-carbon chains are identical and priority is decided by the "junior" branches, so that we have -C(C,H)-CHz-CH2-0 precedes C(C,H)-CHtCHz-H.
Rings are treated exactly as branched chains. In (19) the two groups CHCz of the rings attached to the central carbon atom have priority over CH,; the left hand ring has priority over the right-hand one because working outward one first meets the asterisked positions where C(C,H)-0 > -C(C,H)-H. I n (ZO),
priority. Note that the CIS, being on the "junior" branch, does not in this case affect the result although it is closer to the branch point. Equally, the same procedure is applied if the asymmetric atom is itself part of a ring. In (Zl), for example, the two arms of the rings from *C provide groups a and h.
In theory a t least (the present author knows of no practical case), priority might depend on choice between groups in which the same atom occurs with different valencies, e.g., -NRI and -NRs+, or -NO2 and -NO. In such cases, the lower valence should be made up to the higher by addition of phantom atoms of atomic number zero, thus always in fact giving priority to the atom with the higher valence. Multiple finkings. If an atom is attached to another by a double bond, both atoms are considered to be duplicated;"CH=CHis considered as \
\
-CH-CH-;
and C=O as C-0.
A diagram such
a s ' C 4 makes separate records of the atoms that,
/I
the pairs of asterisked positions are identical; one explores then the prior branches CHOH, and finds the first difference a t Clt, so again the left-hand ring has
I
0 c as one travels along both bonds of the double bond, are met a t their further ends. Triple bonds are represented similarly by triplication, e.g., -C=N by -CN. Series ( A ) and (B) are some examples /\ /\ N N C c of the resnltinc ~rioritvseauences. where the third 6 This procedure was introduced in the third paper, superseding that used in the first two; the change was made largely in order to simplify- the treatment of aromatic rings.
Series ( A ) CHa -COOH OH
I I
>
-Lo
-C-0 0
- L N
>
d t:
I
c
-C(00)-O(C)
Series B -C=N N C
-CC(OC)--O(C)
-CH=NH
I
>
-A=O C
>
-C=CH
-
Ab
N1 CI -C(NH)-N(CH)
-C(NN)--N(CC)
Series (C) -C(CH,)-CH,--CH, CH, H
-&-LC AH,
>
k Volume 41, Number
3, March 1964
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rows show a useful "shorthand" expansion of the groups. Only the unsaturated atom is replicated, not any others in the chain that is being explored. The replica atom is considered as having its valence made up by phantom atoms of atomic number zero, a procedure that automatically assigns lower priority to the replica. An example where this procedure is necessary is shown in Series (C).
The same principle is applied to ethylenic and acetylenic groups in rings, e.g., cyclohexenyl (22) and cyclohexyl(23). Aromatic rings constitute an example of a general situation and when the above procedure is used they can be handled quite simply. When a ring is formed entirely of alternate single and double bonds, forming closed conjugation, mesomeric forms can be written, e.g., (24a) and (24b) for an o-tolyl radical; however, by duplication as just outlined, both these lead to the same representation (24c), and it is unnecessary to choose between forms a and b. Similar simplifications follow for other closed-conjugated systems; the three meso-
(27b) of 2-pyridyl would give different expansions by the above simple method, for (27a) leads to the replicate N on C-2, (27b) leads to the replicate N on C-6); to avoid this the additional principle is used of averaging the atomic numbers among the neighbor atoms of the possible mesomers. Then 2-pyridyl yields an "averaged" expansion (27c)-averaged for C-2 and C-6 between (27aa) [from (27a)l and (2766) [from (27b)], where the numerals are atomic numbers. I n the same way the three mesomeric radicals (28a, b, c ) from the quinolizinium ion give the averaged expansion (2%).
It should be noted that the averaging procedure can be used only for rings containing fully closed systems of alternate single and double bonds. Clearly it could not apply to a radical from, say, 1-methyl-1,2,3triazole (29), where the replica-atoms must be derived from the individual double bonds; equally it must not
7" I
HC-N,
I
"/
be applied when the methyl group is replaced by hydrogen, for the two forms (30a) and (30b) are tautomers, not mesomers; for a given compound one H N
meric forms of 2-methyl-1-naphthyl yield the expansion (25), and 1-azulenyl yields the expansion (26).
HC-N
FC' HC-N,
An additional principle is, however, required when a heteroatom is present in such a closed-conjugated system; for instance, the mesomeric forms (27a) and CH H C F 'CH I II N,\z,CH C
CH H C \~ X!H
II I N\z+CH C
I
I
'
CH ye HC/ 'CH
I
I
I
\NH
HC-N,
of them would have t o be chosen and specified (e.g., by the H convention) in the name. Fortunately such refinements (and some others discussed in the third sequence-rule paper) occur rarely, and it is still rarer that the choice made will affect the sequence-rule symbol R or S, so rare in fact that no actual case is known to the writer and it is even hard t o construct a theoretical one. Although the discussion in this section may have given an impression of complexity, the very great majority of practical cases yield t o quite simple treatment. The examples used above were chosen to provide coverage for the rarer variations possible in the wide sweep of chemistry. The next section gives some examples chosen to illustrate the normal range of practical chemistry. Practical Examples
The first examples must be D-glyceraldehyde (31) and merine (32), for so long the reference substances 120
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for the stereochemical series of carbohydrates and amino acids. Although the answers will be obvious by inspection, let us work out the first case in full detail as it combines much of what has been said in the three proceding sections.
9
CHO
qOOH
b
tive. The RR-symbol may provide a ground on which the two schools can meet.
CHz
I R
b
CHSH 34 R
I n glyceraldehyde (31a) the central carbon atom has attached to it one oxygen atom (atomic number 8), one hydrogen atom (atomic number I), and two carbon atoms (atomic number 6). So the OH group has the highest priority (group a), and the hydrogen atom the lowest (d). Of the two carbon groups, the alcoholic H
/
one can be expanded to - C 4 ;
in the aldehyde
\ H group allowance for duplicates due to the double bond H
I
gives the expanded form -C-0;
I
then the t v o oxygen
I
0 c atoms considered as attached to its carbon atom give the aldehyde group priority over CH,OH where only one oxygen atom is so attached. Thus the priorities are OH > CHO > CHzOH > H, asin (316). I n (316) the lowest group d is in front of the plane of the paper, so we consider the direction of rotation from a to b to c by viewing the model (316) from behind the plane of the paper. This shows that D-glyceraldehyde is (R)-glyceraldehyde. For bserine (32), -NH2 is group a (N has atomic number 7), and H is group d. The carboxyl group, 0
I
expanded to -C-0, II
has priority over CH20H, so II
0 C that formula (32a) can be written as (32b), which is an S-form. Further, the L-series of amino-acids (33) are all Sforms, except for cysteine (34) and related substances in which the sulfur atom of C(SHH) confers priority on C H S H over the C(O00) of the carboxyl group. It is well to note already here that, although the sequence rule is so designed that D = R, and L = S, for the primary didactic compounds of stereochemistry, yet the sequence rule does not necessarily correlate what are customarily regarded as stereochemical series; this point will be elaborated below. Formula (35) is a Fischer projection of dextrorotatory tartaric acid. The dissection shows it to be the RR-form. This result is in formal agreement with Fischer's designation d for this acid, on the basis that the molecule can be constructed from two d-glyceric acid portions; it is not in agreement with the assignment of this acid to the L-series by carbohydrate chemists who regard tartaric acid as a carbohydrate deriva-
The acid whose Fischer projection is (36) has been designated (9) allo-L.-threonine or L,L,-2-amino-3hydroxybutyric acid; the expansion shorn it to be the 2S,3S-form in sequence-rule symbolism. Let us pass now to some cases where the classical D,L system cannot be applied. (+)-Citronella1 has the formula (37). Here H = d ; the C(CHH) groups a t positions 2 and 4 have priority over C(HHH), so the methyl group is c; and the chain CZH2-CLH2-0 has priority over C4HrCJH,C'; from the resulting model shown, (+)-citronella1 is seen to be an R-form.
The formula (380,) for (-)-3-carene can be dissected into (386) and (38c), where the circled number is that of the center whose stereochemistry is being examined. At position 1 (386) the priority order is C,(CCC), CB(CCH), C2(CHH), H, and the configuration is S;
a t position 6 (3%) the priority order is C,(CCC), Cl(CCH), Cs(CHH), H, and the configuration is R. (-)-3-Carene can therefore be designated (lS,6R)-3carene. (+)-Limonene (39a) is a simple illustration of the effect of a double bond in a carbon chain. The partial Volume 41, Number 3, March 1964
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121
expansion (39b) shows that the chain -C3-C~-C1 has priority over -CsCsC1 and leads to the model (39c) and thus to the stereochemical label R.
Perhaps before leaving the terpene hydrocarbons we should look a t one of the rarer more complex cases. Formula (40a) represents one form of 4-carene; the dissection (406) describes the 1- and the &branch from the center C-6. The first pair C1 and C6are both C(CCH); as we work outward the next pairs are, in the 1-branch Cr(CCC) and Cg(CHH), and in the 5branch C4(CCC) and the duplicate C4(ooo) [in (40b) the atom Cgfis the duplicate of Csl. Cr and Ca being equal, Cz gives priority over Cd; that is, branch 1 has priority over branch 5, and this is a 6R-form. It will have been seen that this decision is reached because duplication of atoms is not carried beyond the imaginary atom Cafitself (see above).
Working out becomes much simpler as soon as atoms other than carbon are introduced. For instance, (+)1-phenyl-1,2-ethanediol (41) (10) is obviously the Sform, the oxygen atom of C(0HH) conferring priority H
CHtOH I HO-C-H
H
I
0
"'
HO+H C 41
/c,I
C
b a+-d C
C
over C(CCC) of the benzene ring. Natural (+)eleutherin (42) (11) is equally simply shown by the dissections to be the 9R,11S-form. Even much more complex structures present no great difficulty if they are examined systematically. For example, natural rotenone has structure (43). The dissections, provided they are done systematically, lead quite directly t o the label 6aS,12aS,5'R (12). 122
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Journol of Chemical Education
Natural morphine (IS) also yields easily to systematic treatment, and here too the heteroatoms prove a great help. As formula (44) and the dissections show, the oxygen atoms a t positions 5 and 6 lead to 5R,6S; at position 9, the nitrogen atom is dominant and the dissection to give 9R is simple; a t position 14 the nitro-
gen atom is again helpful in leading to 14R; and a t position 13 the oxygen helps in giving the label 138. Natural morphine is thus completely specified as 5R,6S,SR,13S,14R. I n ar-isosparteine (8) the nitrogen atoms are rigidly held and are chiral centers. As explained earlier, the lone electron pair is considered as a phantom atom of atomic number zero and occupies the fourth tetrahedral position. The stereochemistry a t NI is as illustrated in @a), giving an R label. At position 6 there is the sequence N,, C7(CCH), Cs(CHH), H, leading to 6R. And a t position 7 the sequence is Cs(NCH), Clr(NHH), C8(CHH), H, giving 78. The stereochemistry a t NIB, Cn, and C8is the same as a t NI, Cs, and C7, respectively. This compound is therefore (lR,6R,7S,SS,llR,16R)sparteine.
Use of Sequence-rule Symbols
Restriction to Single Substances. Since, as will have been obvious, use of the sequence rule depends on a geometrical model, it must he applied only to compounds whose absolute stereochemistry has been
determined. Sequence-rule symbols cannot be used to denote relative stereochemistry among series of compounds. A few years ago this might have been held t o be unduly restrictive, but recent advances in many directions have so reduced the time between the determination of relative and absolute configuration that it is better t o wait for definitive knowledge than t o make a wrong guess a t too early a stage. It was noted above that all the usual L-amino acids are S-forms except cysteine and other amino acids with sulfur in the @-position. That will have served as warning that the sequence rule does not necessarily correlate chemical or biogenetic families. It must indeed be stressed that the sequence-rule symbol has nothing to say about family relations. This has the advantage of release from conflicting claims of different series, as in the case of the tartaric acids, but it may sometimes be a disadvantage in a theoretical discussion. Symbolism may be reversed, in particular, on substitution on or near the chiral center; compounds (4547) illustrate this for some glycerol derivatives, as
do (48) and (49) for the steroid series.
A similar warning, that R, S symbols refer only to the compound actually in question, may be necessary when numbering is not continuous throughout a single compound, as arises, for instance, with esters, ethen, and secondary or tertiary amines. For instance, the name for compound (50) should be written his-[(S)-3methoxy-2-methylpropyl] (8)-malate, even though it is the ester of the (R)-alcohol (51) and (8)-malic acid. CHIOCHl H,C+CH~OCO H 50
I
CHaOCHn H,C+CH~OCO--CH, H
OH CH10CH2 H,C+CH%OH H
It has been necessary, in order t o prove that the sequence rule provides a completely general system, t o show that it can be used for all cases, but it has never been maintained that it should be used in all cases. "Local" systems are invented specifically to show family relations in convenient form and, in discussions within those families, there is no need to abandon them in favor of a general system that does not disclose the relationships. However, besides its use when no "local" system exists, that is, even in connection with such families, the sequence rule is of value when different systems overlap or conflict or require complex elaboration, as with the tartaric acids or the threonines (see above), and also when new stereochemical factors cannot be incorporated easily, or a t all, into the local system. Two types of example of the last situation will be given here, illustrating how the addition of R,S-symbols to the "local" names offers convenient solutions. For carbohydrates the local system comprises a set of partial trivial names (gluco-, gala-, araho-, etc.) which, together with a and p for position 1 and D and L for the highest-numbered position covered by the prefix, have sufficed for most of a highly populated section of chemistry. Yet they are not entirely sufficient, for they cannot easily be used for a compound such as (52) and not a t all for a bridged derivative such as (53).
The former can be simply described as (1R)-aldehydoglucose dimethyl monothioacetal pentaacetate, and the latter as (uR)-1,2-o-benzylidene-D-glucitol. I n steroid chemistry a small number of trivial names, together with a,P-prefixes, now used in an absolute sense, suffice for the stereochemistry of a very wide range of compounds, without ambiguity insofar as the ring system can be considered as lying in one plane, that is, for rings A-E of the steroid ring system. The
51
Use in Established Series. The sequence rule can be applied to all optically active compounds. The section of this paper dealing with examples began with well-known simple cases but will have shown how the greatest benefits accrue where other, established systems fail or where none such exists. The preceding section illustrates how it fails to relate chemically or biogenetically similar series. The important questions then arise, nrhether the sequence rule should completely replace the "local" systems such as D,L for amino acids and carbohydrates, and a,@ for steroids and higher terpenes, and, if not, how it is to be reconciled with them.
sequence rule can, however, be useful when substituents on additional spiro rings lie approximately in the plane of A-E ring system; for such substituents cannot be designated or or P as these letters specify that the substituent lies respectively in front of, or behind, the plane of that ring system. Compound (54) illustrates such a situation with respect t o position 25; it can be Volume 41, Number 3, March 1964
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123
named (258)-5P-spirostan or (22R,25S)-58-~pirostan according to whether it is eventually decided that the name spirostan does or does not specify the stereochemistry a t position 22 (14). The sequence rule also offers an alternative to the C Y F , ~ F system (15) for designation of stereochemistry in an aliphatic 17-side chain of a steroid.
Let us now go on from models to compounds. The most obvious example of axial chirality is an allene such as (63), here shown in the R-form. The acid (64) is a historically important example; in it a ring replaces one double bond of an allene; it too is here shown in the R-form.
The Chiral Axis
Of the various types of chirality not covered by the foregoing discussion, that presented by certain allenes and biaryl compounds is sufficiently common to merit description in the present brief account. Suppcse that a tetrahedron (55) be elongated as in (56) ; the chiral center X is thus extended to a chiral axis XY. The conditions needed for chirality (i.e., the condition that a mirror image is not superposable on the original) are then less stringent. For axial chirality in a model (56), it is no longer necessary that all four substitnents be different; it suffices that ligand a shall differ from b, and c from d ; models (57) and (.58), as well as (33, are not identical with their respective mirror images and so the corresponding compounds can exist in optically active forms.
Application of the sequence rule to axial chirality thus requires an additional rule. That rule is: near groups precede far groups. The terms "near" and "far" refer to the pairs as viewed from either end of the axis XY. Suppose that models (56), (57), and (58) are viewed from the point X, then the pairs a-b precede the pair c-d, a-c, or a-b (near Y) ; if the order of priority is a > band a > c> d (as usual), then these models all give the final order of priority as in (59); and, as in the usual procedure, this model is viewed from the side remote from 4; the sequence 1-2-3 then describes an R-form. Alternatively, suppose that these models are viewed from the end Y of the axis; then the pair a-h, i.e., the pair further from Y, has numbers 3-4, and the model (60) is in all three cases obtained. This also is an Rform.
Thus, for axial chirality it is immaterial from which end one views the model; both views give the same sequence-rule symbol; and there is no need to expand the extra rule just given so as to define which end of the axis is near and which far. Of course, model (Fl), which is the mirror image of (58), gives the sequence as in (62) which is an @)-form. 124
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The geometrical situation is similar for biaryls that are subject t o hindered robtion, namely, that four atoms or groups not attached directly to the same single atom are held in planes that make a wide angle with each other. Isomers that owe their separate existence to hindered rotation are conformational rather than structural but, nevertheless, it is often convenient t o distinguish them by the ordinary sequence-rule symbols R and 8. This can readily be done, as follows. In each plane a pair of positions is chosen, as near t o each other as possible,6 such that the two members of each pair can be distinguished from each other by the sequence rule; these yield a model of type (36), (57), or (58) and so afford an R- or an S-symbol in the way explained above. Three examples will suffice. In the form (65) of 3-methoxy-6,6'-dinitrodiphenic acid, one selects the two nearest pairs, K02/COOH, in each ring, and so obtains models (66) which represent an S-form.
In the compound (67) one selects the nearest pairs that describe the situation: in the lower ring the two CHsO groups are indistinguishable and so here the C1/ COOH pair is required; but in the upper ring it is not necessary t o go further from the link than the Originally ( 8 ) the pairs were chosen as near the end of the XY axis as possible. In the third paper (3) this was changed to the method given here, which has advantages in certain theoretically anticipated examples. The change affects only very few known practical cwes.
H/COOH pair, and in this ring the H/OCHa pair does not (by the present procedure" affect the result. Thus an S-symbol applies also to compound (67). Compound (68) appears to be a more complex case but is very simply handled. The axis is l,ll. Position 8a has priority over position 2, and 8'a over 2'. So the model is (69), and the form (68) acquires the symbol R.
Historical and Further Development
As the present paper is only an introduction, describing use of the sequence rule in the more common types of compound without regard t o its theoretical basis, to the course of its development since the original 1951 paper, or to the more recondite types of chirality, the following summary is added to indicate where further aspects are treated, and to avoid apparent contradictions for those who go from the present account to the earlier papers. Paper I [1951,(1)] describes the geometrical approach to the asymmetric tetrahedral center, and the sequence rule itself as applied to ligands differing in atomic composition. I n that paper symbols D and L were used for sequence-rule assignations, with Dglyceraldehyde as reference substance, for a t the time there had not been a single determination of absolute configuration and indeed the amino acid and the carbohydrate series had only just been correlated (16). During the five years between papers I and I1 the absolute configuration of dextrorotatory tartaric acid (17), and by correlation with it also of a very large number of other compounds, had been determined. For this reason, and to avoid confusion with the earlier conventional uses of D and L, the sequence-rule symbols were then changed to R and S. Paper I1 (2) also described application of the sequence rule to ligands which differed only in that one contained a cis and the other a trans grouping, that one was itself in the R- and the other in the S-form, or that the difference between them was only isotopic. The peculiar problems posed by extra symmetry in cyclitols and similar compounds were also considered; and, further, the sequence rule was extended to cover pseudoasyrnrnetry, and axial cases of allenes, spirans, biaryls, etc., and finally planar asymmetry (that is, cases of chirality where neither a center nor an axis of chirality can be found, hut a plane of chirality can be chosen). Thereafter, the increasing use of the sequence rule by chemists and, particularly, its adoption throughout the third supplement of Beilstein's Handbuch der organis-
chen Chemie, indicated certain ways in which the previous treatment needed improvement or expansion. Of these changes, which are described in paper I11 (S), the most important are improved treatments of multiple linkings and aromatic rings, of axial chirality, of cyclitols and related substances, and of some complex situations arising with bridged rings; these improvements are all embodied, so far as necessary, in the preceding sections of the present paper which thus presents the sequence rule in its most modern form. More importantly, novel parts of paper 111 are the introduction of the terms chirality and chiral, and extension of the sequence rule procedure to chiral octahedral structures, to conformations up to ligancy four, and to helical secondary structures (as in proteins). Acknowledgment
I am much indebted to Sir Christopher Ingold, Professor G. R. Pettit, and the Editor for comments on the manuscript. Literalure Cited ( 1 ) CAHN,R. S., AND INGOLD, C. K., J. Chem. Soc., 1955, 612. ( 2 ) CAHN,R. S., INGOLD, C. K., AND PRELOG, TI., Experientia, 12, 81 (1956). C. K., A N D PRELOG, V., Anyew. ( 3 ) CAHN,R. S., INGOLD, Chem., in press. ( 4 ) CONDON, F. E., AND MEISLICH, H., "Introduction to Oraanic Chemistrv." Holt. Rinehart and Winston Cam; p. 499. ;any, New ~ o r k 1961, G. S., "Organic Chemistry," ( 5 ) CRAM,D. J., AND HAMMOND, MeGraw-Hill Book Company, New York, 1959, p. 144. M.,"Topics in Organic Chemis( 6 ) FIESER,L. F., AND FIESER, try," Reinhold Publishing C o p , New York, 1963, p. 422. "Baltimore Lectures," C. J. Clay and Sons, ( 7 ) LORDKELVIN, London, 1904, pp. 436, 619 (lecture delivered in 1884, revised later); cf. WHYTE,L. L., ~ V a t u ~ (London), e 180, 513 (1957); 182, 198 (1958). A. P., AND POTAPOV, V. M.,Tetrahedron, 1, ( 8 ) TERENTIEV, 119 (1957). ( 9 ) International Union of Pure and Applied Chemistry, Comptes rendus of the 15th (1949) and 16th (1951) Conferences. (10) PEELOG, V., WILHELM, M., AND BRIGHT, D. B., Helv. Chim. Acta, 37, 221 (1954). (11) SCHMID, H., AND EBN~THER, A,, Helu. Chim. Ada, 34, 1043 (1951). L., GODIN,P. J., KALTENBRONN, ( 1 2 ) Biicm, G., CROMBIE, J . S.. SIDDALINGALAH. K. S.. AND WHITING. D. A.. 6. Chem. Soe., 1961, 2843. R. K., AND CALDWELL, H. M. E., J . Chem. Sac., (13) BENTLEY, 1955, 3261. G. P., AND PETTIT,G. R., Ezperienlia, 18, 404 (14) MUELLER, , R., Ezperiatia, 19, 124 (1963). (1962); cf. P E ~ I TG. I am much indebted to the authors far preview of these papers. (15) International Union of Pure and Applied Chemistry, Information Bulletin No. 11, 1960, p. 50; FIESER, L. F., AND FIESER,M., Tetmhedron, 8, 360 (1960). P., HUGHES, E. D., INGOLD, C. K., AND RAO, (16) BREWSTER, P. A. D. S., Natu~e( L a d o n ) , 166, 178 (1950). A. F., AND V O N BOMMEL ( 1 7 ) BnvoE~,J. M., PEERDEMAN, A. J., N o t w e (London), 168,271 (1951).
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