MOLECULES IN THE "NEWS"
RajanBabu
Selectivity versus Specificity
When a chiral center or a double bond is generated in a molecule there is the possibility that both
configurations may result. However, some reactions are selective and yield unequal amounts—or
sometimes only one—of the two possible stereoisomers. The terms ′stereoselective′ and ′stereospecific′
are often used interchangeably—and often incorrectly—to describe these events. Indeed, there is a
remarkable degree of confusion in the chemical literature regarding the use of these terms. Apart from a
1-6,9
few notable exceptions
most undergraduate textbooks make only vague reference to this topic or steer
clear of it altogether, and it is surprising that organic chemists have tolerated this unsatisfactory state of
affairs for so long. The terms ′regioselective′ and ′regiospecific′ are also widely abused and require
clarification.
Stereoselectivity and stereospecificity
1
According to Eliel a reaction is described as stereoselective if one (or more) of a possible set of
stereoisomers is (are) produced in excess, whereas a reaction is described as stereospecific if different
stereoisomeric starting materials yield different stereoisomeric products. These formal definitions
are illustrated by the examples shown in (a) and (b). However, confusion arises because the term
stereospecific has also been used to describe reactions which are completely stereoselective. To quote
from Eliel, ′the use of one technical term to denote a semi-quantitative modulation of another term seems
undesirable, since it is not clear how high stereoselectivity must be before it is called stereospecific′.
Stereoselective (No meso product from trans-2-butene)
H
HO
O4
KMn
- OH
OH
H
+
HO
H
H
OH
(D/L)
H
H
OH
OH
(meso)
Stereoselective (a)
S
OH
R
R
S
OH
OH
OH
OH
S
R
OH
Stereoselective (No meso product from cis-2-butene. Only meso product from cis-2-butene; verify!!)
KMnO4
-OH
H
H
OH
OH
(meso)
These reactions are also stereospecific, since each stereoisomer gives different products (trans
giving D/L-diols and cis giving meso-diol)
Some further examples of stereoselective reactions are shown in (c) and (d). Stereoselectivity can
clearly be observed in various degrees and reactions can be said to be ′highly stereoselective′ or
1,2
′moderately stereoselective′ etc.
Whether the same qualification can be applied to stereospecificity is
7
perhaps a more debatable point.
H
CH3
H2
PtO2
CH2
H
CH3
CH3
+
(c)
CH3
H
CH3
32 percent
H
68 percent
CO2Me
+
H
!
CO2Me
H
CO2Me
CO2Me
75 percent
CO2Me
+
H
CO2Me
(d)
H
25 percent
Some other examples of stereospecificity are shown in (e) and (f). Make models and see why you get
different products in examples shown in (e). Remember the E-2 eliminations proceed through transperiplanar transition states (example shown in box). A more general definition of stereospecificity
2
that has been adopted in some quarters defines a stereospecific reaction as one in which
stereochemically different molecules react differently. This definition then includes the possibility that
they may either yield (i) stereoisomeric products or (ii) react at different rates, or (iii) yield products that
differ in ways other than stereochemistry. According to this interpretation it would seem that almost all
reactions of stereoisomers are stereospecific. I DO NOT ENCOURGE USING THIS DEFINITION
EXCEPT IN THE CASE OF KINETIC RESOLUTIONS (i.e., When the rates of stereoisomeric starting
materials are different).
I–
H
H
Br
H
I-
H
Me
Me
Br
Br
H
Br
H
I-
AcO-
AcO
H
(R)
(e)
H
Br
OTs
(S)
(f)
H
OTs
AcO-
AcO
H
Br
(R)
(S)
(SN2-Inversion)
It is generally accepted that all stereospecific reactions are stereoselective but not all
1,3,4
stereoselective reactions are stereospecific.
Some reactions that are stereoselective but not
stereospecific are (g) and (h).
OH
CH3
C C
H
H
H3C
CH3C!CCH3
H2
ar
Lindl
Na
NH
3
i
Pr ) 3
Al(O
O
(g)
LiAlH
(
(h)
OBu i
)
3
OH
H
C C
CH3
H
H3C
However, if the wider definition of stereospecificity were adopted, then we must also accept the
possibility that while some reactions are stereselective but not stereospecific, (g) and (h), some reactions
2
are stereospecific but not stereoselective, eg. (i) and (j).
For other examples, see ref. 9. Schemes 2.9 and 2.10.
OH
N
OH
H+
Cr O
3
OH
O kcis
= 3.2 (i)
ktrans
Cr O 3
HO
Ph
Me
Ph
N
Me
Me
O
O
H+
Ph
Ph
H
N
Me
(j)
N
H
(Beckmann Rearrangement)
The formation of maleic anhydride by heating fumaric and maleic acids presents an interesting case.
4
This has been described as an example of a reaction that is stereoselective but not stereospecific.
However, adopting the wider interpretation of stereospecificity suggests that this reaction should be more
correctly classified as stereospecific but not stereoselective, since there is indisputably (?) only one cyclic
anhydride of butenedioic acid and it will certainly be formed at different rates from the two possible
starting materials.
2
To quote from Morrison and Boyd, ′stereoselectivity is concerned solely with the products of a
reaction, whereas stereospecificity is concerned with the reactants, each of which behaves in its own
specific way′. Stereospecifity has mechanistic implications. The terms ′product selectivity′ and ′substrate
8
selectivity′ have also been used in this context.
The prefixes enantio- and diastereo- can clearly be used to qualify both of the terms selective and
specific. However, it should be remembered that whereas enantioselective, for example, implies that one
enantiomer is preferentially formed as product, enantiospecific indicates that two enantiomeric reactants
(or including catalysts) react differently—eg to give stereoisomeric products, as in (f). Furthermore, by
using the definition of stereospecificity given by Morrison and Boyd, kinetic resolution is simply an
example of enantiospecificity.
Regioselectivity and regiospecificity
What then can we say about the use of the terms regioselective and regiospecific? While there seems
to be no dispute about the meaning of regioselective, a clear definition of regiospecific seems more
elusive. By analogy with the above stereochemical definitions, a reaction should be described as
regioselective if one or more of a possible set of constitutional (structural) isomers are produced in
excess, while a reaction will be regiospecific if different constitutional isomers of the starting material give
different constitutional isomers of the product, or more generally, behave differently. Some examples are
the reactions (k, l, m, n).
CH3
BR2
BH 3
T HF
CH3
HNO3
Regioselective (k)
CH3
NO2
Regioselective (m)
+
H2SO4
NO2
BR2
OSiMe3
O
(ii) PhCHO
TiCl4
CH(OH)Ph
(ii) H2O
BH3
THF
BR2
OSiMe3
Regiospecific (l)
BH3
THF
O
(i) PhCHO PhCH(OH)
TiCl4
Regiospecific (n)
(ii) H2O
BR2
Recommendations
We are faced with a number of possible options. One is obviously to adhere strictly to the definitions
of stereoselectivity and stereospecificity given by Eliel. A second would be to adopt the more general
definition of stereospecificity advocated by Morrison and Boyd. However, since this implies that all
reactions of stereoisomers are stereospecific, it is not very helpful. A third possibility would be to
adopt the ′anti-Eliel′ view that stereospecific means 100 percent stereoselective, but this is an
unnecessary distinction and creates problems in deciding which reactions qualify (ie where to draw the
line). While this analysis might seem to make a very good case for avoiding the use of the term
stereospecific altogether, my own preference and recommendation would be to retain and adhere to
the definition given by Eliel.
The term regiospecific as defined here is of limited utility and its use to denote 100 percent
regioselectivity is both unnecessary and unsatisfactory, for the same reasons. In this case, therefore, the
most sensible approach might well be to declare the term redundant. Certainly care should be exercised
in using it, and surely both authors and referees should be more precise about the stereochemical and
regiochemical terminology used in papers and textbooks.
Based on an article by Dr. Robert S. Ward in Chemistry in Britain (?)
References
1. E. L. Eliel, Stereochemistry of carbon compounds, p 436. New York: McGraw-Hill, 1962.
th
2. R. T. Morrison and R. N. Boyd, Organic chemistry, 5 edn, p 343. Boston: Allyn & Bacon, 1987.
3. K. P. C. Volhardt, Organic chemistry, p 200. New York: Freeman, 1987.
4. A. Bassindale, The third dimension in organic chemistry, p 142. New York: Wiley, 1984.
5. S. Warren, Organic synthesis: the disconnection approach, p 96. New York: Wiley, 1982.
rd
6. J. March, Advanced organic chemistry, 3 edn. New York: Wiley, 1985.
7. S. G. Davies et al, Chem. Br., 1989 25, 259.
8. M. Nogradi, Stereoselective synthesis, Weinheim: VCH, 1987.
9. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Parts A and B, 4th Ed.; Kluwer/Academic
Plenum: New York, 2001.