CH 391: UNIT 3: STEREOCHEMISTRY

I.Stereochemistry of Nucleophilic Substitution Reactions at

Saturated Carbon
Nucleophilic substitution at saturated carbon is a very common and useful
reaction type. These reactions are found to occur via two distinct mechanistic types,
which are designated SN1 and SN2. The stereochemistries associated with both of
these mechanistic types will be discussed, beginning with the SN2 reaction.

A.The Stereochemistry of SN2 Reactions. The symbol SN2 refers to “substitution,

nucleophilic, bimolecular”. The designation bimolecular refers to the number of
molecules in the rate-determining step. Generalized examples of SN2 reactions are
represented below, recognizing that the nucleophile may be negatively charged or
uncharged and the leaving group (when present in the substrate) may be uncharged or
positively charged.

Whatever the charge type of the nucleophile or the leaving group, these
reactions invariably occur with complete inversion of configuration at the saturated
(sp3) carbon undergoing substitution. One of the earliest (and especially elegant)
demonstrations of inversion of configuration in an SN2 reaction is illustrated in the
reaction of optically pure 2-iodooctane with radioactive iodide ion. The observed
reaction,t he incorporation of radioactive iodine into the substrate, is rigorously
second order (first order in iodide ion and first order in iodooctane), as it should be for
an SN2 mechanism. The key observation is that the rate of incorporation of radioactive
iodine into 2-iodooctane is exactly one-half of the rate of racemization of the optically
active substrate. This can only be the case if each reaction of radioactive iodide ion
with 2-iodooctane racemizes two molecule of this substrate. In turn, this can only be
the case if each reaction occurs with inversion of configuration, the inverted product,
combined with a molecule of the original product, then provides two molecules of
racemic (R + S) 2-iodooctane. If the reaction had occurred via a carbocation route,
racemization would have been the result of each reaction with radioactive iodide ion,
making the rate of racemization exactly equal to the rate of radioactive iodide ion
incorporation.
 Of course the determination of absolute configurations of reactants
and products now makes the determination of reaction stereochemistry
relatively straightforward. The theoretical question of especial interest is
why the preference for inversion over hypothetical retention is so powerful
in all of these reactions. Incidentally, it clearly has nothing fundamentally
to do with the circumstance that a negatively charged nucleophile may
electrostatically repulse a leaving group, which in the molecule is uncharged
but which is also in the process of becoming negatively charged in the
transition state, in a retentive mechanism, since inversion is still strongly
preferred even when the leaving group (when present in the molecule) is
positively charged and the entering nucleophile is negatively charged
(resulting in an electrostatic attraction). The theoretical baisis for the highly
developed preference for an invertive reaction mechanism can be seen by
applying either the concept of transition state aromaticity/antiaromaticity or
by applying frontier orbital (HOMO/LUMO) theory. The former approach
has already been developed, and for the specific case of nucleophilic
substitution, in Unit 1. The explanation given there was that the transition
state for retentive substitution is unavoidably a cyclic one and it possesses
four electrons (two from the nucleophile and two from the C-L bond), so it
is antiaromatic, whereas the transition state for the invertive process is
acyclic, so that this TS is non-aromatic.

Let’s now consider the application of HOMO/LUMO (or FO) theory ,

which was also developed in Unit 1, to the specific case of bimolecular
nuceophlic substitution. The electron pair being donated clearly must come
from the nucleophile; so the HOMO is the orbital of the nuceophile (Nu)
which contains the unshared electron pair used to bond to carbon. But what
about the LUMO? Clearly, the substrate molecule must supply the LUMO.
Since the bond being broken is the C-L bond, the appropriate LUMO must
be that of this bond. Recalling that this antibonding LUMO of the C-L bond
has a node in the center part of the bond, we can see from the illustration
that whereas the nucleophile can bond to the carbon end of the bond, as it
needs to, it cannot at the same time bond to the L part of the bond. The
spatially unavoidable interaction with L is in fact antibonding, and tends to
diminish the net bonding interaction of the nucleophile with the organic
substrate. In contrast, if the nucleophile enters from the backside of the C-
L bond, it is quite remove from L and there is no significant antibonding
interaction to interfere with the bonding interaction between the nucleophile
and carbon. It is important to realize that, although bonding interactions
between the nucleophile orbital and both the carbon and L orbitals are
possible if we use the C-L BMO, this interaction would be between two
filled orbitals, and thus can yield no net stabilization. Remember that this is
because in the interactions between two filled orbitals, there are four
electrons to accommodate.

TS for the Hypothetical Retention Mechanism

B. The Stereochemistry of SN1 Reactions. The generalized mechanism for an SN1

reaction is illustrated below. In it the rds is heterolysis of the C-L bond, resulting in
the formation of an intermediate carbocation. The planarity of this latter ion typically
results in the its reaction, in approximately or exactly equal amounts from either face,
giving approximately equal amounts of retention and inversion, also described as
racemization.

In a few cases, a slight excess of inversion over retention is observed

(e.g., 90% racemization, 10% inversion), presumably as a result of weak
“blocking” of the front face of the carbocation by the leaving group.

C. Retention in SN Reactions.. In a number of special cases, the stereochemical result

of SN Reactions is pure retention. These cases are of special interest because neither of
the typical SN mechanisms provides for retention. One such reaction is the conversion
of 3-bromo-2-butanol to 2,3-dibromobutane by reaction with hydrogen bromide.
When the (2R,3S) stereoisomer of this alcohol (the carbon atom bearing the hydroxyl
group is C2 and that bearing the bromo group is C3) is treated with aqueous hydrogen
bromide, meso-2,3-dibromobutane is produced diastereospecifically. Note that the
overall result is the replacement of the alcohol function by bromine with retention of
configuration, since inversion (as in an SN2 mechanism) at the alcohol carbon
(C2)would have given the (2S,3S) stereoisomer of 2,3-dibromobutane (the
configuration at C3 remaining fixed, of course). On the other hand, reaction via an
SN1 mechanism would have given a mixture of 2S,3S and 2R,3S stereoisomers, i.e., a
mixture of the meso diastereoisomer and the optically active 2S,3S enantiomer. This
follows from the fact that a carbocation mechanism would have left the configuration
at C3 unaltered, but given a mixture of the R and S configurations at C2. The actual
result, retention of configuration, can be clearly seen in the illustration below by
simply comparing the structures of the reactant and product in the Newman
projections provided.

In contrast, the (R,R) and (S,S) stereoisomers of the bromoalcohol both afford
a racemic mixture of (2R,3R) and (2S,3S)-dibromobutane. This amounts to retention
of configuration in the conversion of the (2R,3R) alcohol stereoisomer to the (2R,3R)
dibromide, but in inversion of configuration at both C2 and C3 for the conversion of
the (2R,3R) alcohol to the (2S,3S) dibromide. All of these results are readily and
uniquely explicable if it is assumed that bromine acts as a neighboring group (i.e., as
an intramolecular nucleophile), displacing the leaving water molecule from C2 with
inversion of configuration (as in a normal SN2 reaction) thus forming an intermediate
epibromonium ion. The latter then opens up by reaction with the external nucleophile
(bromide ion), as epibromonium ions do in what is essentially an SN2 reaction, with
inversion. Since the epibromonium ion formed from either the (R,R) or (S,S) alcohol
is achiral (it has a plane of symmetry which bisects the central C2-C3 bond), it can
react with bromide ion at either carbon (the one which formerly was C3 or the one
which formerly was C2) equally to yield the two enantiomers of 2,3-dibromobutane.
The distinct epibromonium ions derived from the (2R,3S) and (2S,,3R) alcohol are
chiral (do not have a plane or other relevant element of symmetry), but their reaction
produces meso-2,3-dibromobutane, which is achiral. Thus, the products of all of these
reactions are optically inactive, even though they are formed from enantiomerically
pure starting alcohols.
 Analogous results are found in other reactions in which a
suitably placed substituent having an unshared electron pair is present in the
molecule (e.g., alkoxy, alkylthio, and amino, and amido substituents. Even
certain electron-rich aryl substituents
(e.g. 4-methoxyphenyl = anisyl) are found to act as effective neighboring
groups, e.g., in the solvolysis (cleavage of solvent) of the 3-anisyl-2-butyl
tosylates, shown below. Note that the erythro/threo nomenclature for
distinguishing diastereoisomers is convenient to use here. The erythro
isomer of a compound containing two non-equivalent stereocenters is the
one (like erythrose) in which all of the like groups can be placed anti to one
another in one of the conformations accessible to the molecule. In the case
under discussion, hydrogens are anti to hydrogens, methyls to methyls, and
the tosylate (4-methylbenzenesulfonyloxy) and anisyl groups (the “like”
groups which are not identical) are also anti. In the single product obtained
in the acetolysis (solvolysis in acetic acid), the like groups are still anti to
one another, i.e., only the erythro isomer is obtained.
 Further, only one enantiomer of the erythro diastereoisomer is
obtained, since neither the intermediate arenium ion nor the product are
achiral. In other words, both enantiomers of the erythro diastereoisomeric
tosylates give different, enantiomerically pure products which are the result
of retention of rigorous configuration at both stereocenters. In
contrast, either threo enantiomerr gives an intermediate arenium ion which
has a plane of symmetry and is therefore achiral. It generates racemic threo
acetate (a 50:50 mixture of the 2R,3S and 2S,3R enantiomers). See if you
can draw this out and show the structures of the two enantiomers of the
threo product.Incidentally, the cationic intermediate in these reactions has
been called a “phenonium ion”by Professor D.J.Cram, in whose research
group this work was performed. It is a special kind of arenium ion, i.e., the
type of cationic intermediate which is involved in electrophilic aromatic
substitution. Finally, the participation of an internal nucleophile in the rds
naturally results in rate enhancements in comparison to direct reactions with
external (solvent) nucleophiles.
In certain rigid bicyclic systems, such as the bicyclo[2.2.1]heptyl system (the
norbornyl system), even alkyl groups can act as neighboring groups. This is
illustrated in the acetolysis of optically pure exo- 2-norbornyl tosylate, which results
in the formation exclusively of the exo isomer, but in racemic form. Obviously, an
SN2 reaction would result in the formation, exclusively, of the endo acetate, whereas
an SN1 reaction should result in the formation of a mixture of endo and exo acetates.
Importantly, in the case of either of these mechanisms, an single enantiomer would
result, i.e., optically active products would be formed. Instead, only the exo product is
obtained, and it is 100% racemic. This results stem from neighboring group
participation by the C6 carbon atom to form a symmetrical (i.e., achiral), bridged
cationic intermediate, which has been called a nonclassical carbocation. The latter can
react at either of two equivalent carbon atoms (formerly C2 and C1) to yield both
enantiomers of the exo acetate in equal amounts.

II. Stereochemistry of Additions to Alkenes

Additions to alkenes can proceed via three reqasonably distinct stereochemical
outcomes, viz., anti stereospecific, syn stereospecific, and non-stereospecific
addition., as indicated in the illustration given below. In anti stereospecific additions,
the two new bonds to the unsaturated carbon atoms of the alkene are formed from
opposite faces of the pi bond. In syn stereospecific additions, the new bonds are
formed exclusively from the same face of the pi bond. Finally, in non-stereospecific
addition, a mixture of syn and anti addition occurs.

A. Additions Involving Carbocations. Many additions to alkene pi bonds

proceed via intermediate carbocations. In such cases the stereochemical consequences
are exactly the same as in SN1 reactions, viz., non-stereospecific reaction. Familiar
instances are the additon of HCl to alkenes and the acid-catalyzed hydration of
alkenes. The addition of hydrogen chloride to 1,2-dimethylcyclohexene is provided as
an illustration. The intermediate carbocation is able to react from either face of the
carbocation with near equal facility, giving both the cis and trans products. Since the
product chlorides are diastereoisomeric, the transition states leading to them are
diastereoisomeric, also, and thus have unequal energies. Consequently, they are not
formed in exactly equal amounts. However, the amounts differ only slightly, since the
reaction of the carbocation with chloride ion (or water) is highly exothermic,
providing for a transition state which doesn’t have very much product character.

The question of why the reaction does not occur via a concerted, syn
stereospecific path, instead of the stepwise carbocation path is an interesting one. The
carbocation path involves a rate-determining step in which two bonds are broken and
only one is formed. It is strongly endothermic. On the other hand, the concerted
addition pathway would forrm two bonds and break two bonds and is obviously
exothermic. Why is the stepwise path, which appears to be less favorable from a
thermodynamic standpoint, actually the lower energy pathway. If we look at the TS
for a concerted addtion of HCl to a pi bond we can see that the TS has antiaromatic
character, i.e., it has a cyclic system which contains four electrons. Consequently, the
stepwise path is of lower energy. It should be noted that concerted addition of HCl to
1,2-dimethylcyclohexene would give only the cis chloride product (i.e., the product in
which the methyl groups are cis o each other on the cyclohexane ring).

Obviously, acid-catalyzed hydrations of alkenes are similarly non-

stereospecific, since they also involve intermediate carbocations.
B. Anti Stereospecific Additions to Alkenes. In sharp contrast to the acid-catalyzed
hydration of alkenes and hydrogen halide additions to alkenes, the additions of
halogens to alkenes occurs with rigorous anti stereospecificity. This stereospecificity
immediately notifies us that intermediate carbocations are not involved. Nor is the
addition likely to be concerted, since concerted additions to alkenes should result
in syn stereospecificity. Anti stereospecificity results from the initial addition of one
bromine (the electrophilic bromine) to the pi bond, followed by the opening of this
intermediate epibromonium ion from the opposite face by bromide ion. The
stereochemistry of this opening is exactly as expected, since it is essentially an SN2
reaction, involving bromide ion as the nucleophile and the bridging bromonium as the
(internal) leaving group, which leaves from the face opposite to that of the entering
nucleophile. Recall that frontside displacement of the leaving group (with the
resulting syn stereospecific addition) would involve a cyclic, four electron
(antiaromatic) system. The addition of chlorine and iodine to alkene pi bonds also
occurs via an anti stereospecific route.

In contrast, the addition of bromine (and other halogens) to alkenes in which

the prospective carbocation intermediate is stabilized by an electron donating or
conjugating group does not usually occur via an exclusively anti stereospecific route.
Apparently, the initially formed bromonium ion is able to partially equilibrate with
the relatively stable open carbocation, which then can reclose, prior to reaction with
bromide ion, to the diastereoisomeric epibromonium ion, thus leading to a mixture of
the two diastereoisomer products. This is usually particular noticeable for the cis
alkene because the epibromonium ion corresponding to the cis alkene is less stable
(steric repulsions) than the trans diastereoisomer. One reason the reaction is still
considered to proceed initially via the epibromonium ion is that trans-stilbene yields
essentially only the meso dibromo compound, via anti stereospecific addition.
Regiochemistry of Bromine Addition to Alkenes. In the bromination of alkenes, the
two bromine atoms introduced into the molecule enter into the mechanistic pathway
in entirely different roles. One enters electrophilically and the other as the
nucleophilic bromide ion. Unfortunately, these two bromines can not be distinguished
in the final product, so that even in additions to unsymmetrically substituted alkenes,
the regiochemical preference of bromination cannot be directly determined. The
question being explored here is as follows: in the reaction of bromine with an
unsaturated alkene such as propene, does the nucleophile enter in selectively a the
primary carbon or the secondary carbon of the alkene or does it, in fact, enter
unselectively. The answer, which we can determine indirectly, but decisively, is that it
enters with a high degree of selectivity onto the more hindered, secondary carbon.
The conventional experimental determination uses the reaction of bromine with an
unsymmetrically substituted alkene in aqueous solution, where the same
epibromonium ion is formed as an intermediate, but this intermediate reacts
extensively with the more abundant water molecules to give a bromohydrin, i.e., a
bromoalcohol. In the case of propene, as is illustrated below, the result is selective
formation of 1-bromo-2-propanol, rather than 2-bromo-1-propanol. It is presumed that
nucleophiles in general prefer this entry mode, and this is supported by an analysis of
the reasons for this manner and high degree of regiospecificity. Incidentally,
analogous results are obtained even in the addition of aqueous bromine to a 1,1-
disubstituted alkene such as isobutene, where the competition is between a tertiary
carbon and a primary carbon. The nucleophile strongly prefers to react at the more
highly substituted (more sterically hindered!!) carbon.

To analyze the fundamental reasons for the somewhat surprising

regiochemical preference in the opening of the bromonium ion, we should first
consider the structure of the epibromonium ion intermediate. This is especially
important because the second step fo the reaction, that in which the epibromonium ion
is opened by a nucleophile, is highly exergonic (the epibromonium ion is not so much
more stable than an analogous carbocation). Consequently, an applicationi of the
Hammond Principle indicates that the transition state for this reaction step should
more closely resemble the reactant in this step, which is the epibromonium ion. In
general, the cationic species which we call an epibromonium ions has three
reasonable resonance (canonical) structures. Only one of these is a bromonium ion
structure (see below), while two carbocation structures also contribute to the
resonance hybride. Consequently, the epibromonium ion has both bromonium ion
character and carbocation character at both carbons of the original double bond. In the
case of an unsymmetrically substituted alkene such as propene, the two canonical
carbocation structures are not of equal energy, and resonance theory requires that the
hybrid (real) species more closely resemble the lower energy structure. In the
resonance treatment of the epibromonium ion derived from propene, the structure
labeled a has positive charge at a secondary carbon. It is therefore of lower energy
than the structure c, which has positive charge at a primary carbon. The real, hybrid
species therefore more closely resemble structure b, so there is more positive charge
at the secondary carbon than at the primary carbon. The short form of the rationale for
the attack of the nucleophile at this carbon is that ions typically react at the site of
highest charge density. This is expected because the reaction of an epibromonium ion
with a nucleophile is exothermic, so that the TS of the second step of the reaction also
resembles the epibromonium ion (rather than the product of that step). This implies
that covalent bond formation hasn’t proceeded very far, so that the nucleophile-to-
carbon bond is still long and largely ionic. There are two important insights from this
picture. First, the knowledge that a long and weak covalent bond exists in the TS
suggests that steric effects should be quite small. Thus the distinction between
tertiary, secondary, and primary carbons on the basis of steric effects (which
consideration is dominant in SN2 reactions) is at most slight. Secondly, the ionic (or
electrostatic) nature of the bonding will be strongest when the fractional positive
charge is largest, which it is on the secondary carbon in the present instance. It is
interesting to note that these regiochemical considerations remain valid even when the
choice is between a tertary and a primary carbon, as in the case of the reaction of
isobutene with bromine in aqueous or alcoholic solution.

Invoking the Method of Competing Transition States, as illustrated below, the

TS for reaction of the nucleophile at the secondary carbon is favored because:

 The reaction step is exothermic, so the TS closely resembles the

epibromonium ion plus bromide ion. Consequently the covalent bonding
between the bromide ion and the appropriate carbon is weak and long in the
TS. As a result, steric effects, as between secondary and primary carbons are
minimal.
 Since the TS is much like the epibromonim ion, and the covalent bonding is
weak, the main source of bonding interaction between the nucleophile and the
appropriate carbon of the epibromonium is is ionic or electrostatic bonding.
Such bonding should be stronger the larger the fractional positive charge on
the carbon atom. Thus the interaction with the larger partial positive charge on
the secondary carbon is stronger than that with the smaller partial positive
charge on the primary carbon.
 Oxymercuration. Another alkene addition which proceeds
with anti stereospecificity ( in the case of simple alkenes), is oxymercuration. The
addition of mercuric acetate to alkenes in aqueous solution proceeds to yield a -
acetoxymercuri alcohol. The latter can be reduced to the simple alcohol using sodium
borohydride. The overall result of oxymercuration/reduction is anti stereospecific,
Markovnikov (regiochemistry) hydration of an alkene (without encountering
carbocation rearrangements). The latter regiochemical feature is illustrated below in
the oxymercuration of the unsymmetrically substituted alkene, propene. A further
advantage of this indirect hydration method is that skeletal and hydride
rearrangements do not occur, because carbocation intermediates are not involved. As
in the case of bromination, the anti stereospecificity is the result of the opening of a
bridged mercurinium ion from the opposite face in a nucleophlic substitution reaction.
Syn Stereospecific (Concerted) Additions. Additions to alkenes which proceed with
syn stereospecificity are nearly always concerted additions. A familiar example is
hydroboration, that is, the reaction of an alkene with borane to yield an organoborane.
Oxidation of the organoborane in situ with alkaline hydrogen peroxide yields an
alcohol, with net syn stereospecific addition of water to the double bond, without the
troublesome rearrangements which accompany carbocation mediated reactions, and
with opposite regiochemistry (anti-Markovnikov) to that observed in acid-catalyzed
hydration.

The resonance treatment of the transition state for this reaction has already
been given in Unit 1, but is repeated here. Note that in the TS the hydrogen which is
being transferred to carbon from boron is still partially linked to the boron atom.
Consequently, the formation of the new C-H bond and the new C-B bond must take
place from the same face of the pi bond. It would be geometrically impossible for the
hydrogen to be transferred to the opposite face of the pi bond while still maintaining
significant bonding to boron. Essentially, this is why syn stereospecific reactions are
almost always concerted reactions and conversely, i.e., concerted mechanisms
essentially always result in syn stereospecific addition.
 There is another interesting aspect of this hydroboration reaction. Since we
seem to have a cyclic TS with four electrons (two from the pi bond and two from the
B-H bond), this would seem to set up an antiaromatic TS, which should be strongly
disfavored. In fact, this TS is not rigorously cyclic when viewed in terms of the orbital
overlaps. In particular, the 2p AO on the carbon which is bonding to boron is bonding
to a 2p AO on boron, but the hydrogen which is being transferred to carbon is bonded
to boron via another AO (a boron sp2 AO) which is orthogonal to (has zero overlap
with) the 2p AO on boron. Consequently, the overlaps of the system do not continue
through boron, which acts as an insulator between the hydrogen and the carbon to
which boron is bonding. Consequently, it should be recalled that not all four-
membering ring transition states necessarily are antiaromatic.

Carbene Additions. Carbenes are species containing divalent carbon. The

addition of the simplest carbene (CH2also called methylene) or substituted carbenes to
alkenes is an interesting and preparatively useful reaction. Dichlorocarbene (CCl2) is
an especially readily available carbene which, although not isolably stable, can be
conveniently generated in situ for preparative purposes. Since the divalent carbon is
uncharged and has only two covalent bonds, there are two additional valence shell
electrons to be distributed between the remaining two valence shell orbitals. They can
both go into the same AO with spins paired (singlet carbene) or into different AO’s
with unpaired spins (triplet carbene). Although the ground state of the parent carbene
is a triplet, both states can be accessed, depending upon the mode of preparation. The
ground state of dichlorocarbene, however], is a singlet. The unshared pair of electrons
occupies a hybrid orbital, leaving the higher energy 2p AO vacant. The additions of
this substituted
carbene to alkene pi bonds, as noted earlier, have been studied and used extensively.
The addition, which forms two new carbon-carbon bonds, while breaking none, is
highly syn stereospecific. For example, the addition to cis- and trans-2-butene afford,
respectively, the cis- and trans cyclopropanes, as shown below.

The rigorous syn stereospecificity suggests that the reaction is

concerted, and theoretical calculations strongly support this conclusion.
There are several unique aspects of this reaction path which deserve our
attention. First of all, the reaction is an example of a relatively rare class in
which the enthalpy of activation appears to be nil or vanishingly small.
Entropy effects, however, do appear to play some role in defining the
modest selectivity of carbene additions. The second novel aspect of this
cycloaddition reaction is that it takes place via a non-least motion pathway
in which the orientation of the carbene with respect to the alkene is
drastically different from its orientation in the final, cyclopropane
product. This is because the approach of the carbene to the alkene in a
geometry which closely resembles that of the product would contain an
antiaromatic 4 electron cyclic array. In contrast, theun-productlike approach
has a two electron, aromatic cyclic array. Consequently, in the least energy
pathway the carbene fragment must, somewhere along the reaction path,
rotate a full 90 degrees to provide the ground state geometry of the
cyclopropane product. This rather extreme motion is, however, performed
subsequent to the transition state and after rather strong bonding has already
been initiated, so that it is not problematic in regard to activation energy.
 Since the carbene fragement has two AO’s, there is actually a second
cyclic array present in either pathway. For example in the disfavored path
(the one shown on the right above) there is also another cyclic array, one
involving the vacant 2p AO (see below). Since the pi bond contains 2
electrons, this constitutes a 2 electron cyclic array, and would seem to
represent an aromatic array. Quite the opposite is true, however. The array
which involves the 2p AO is what is known as a Mobius array. A Mobius
cyclic system is one which has one or an uneven number of nodes in the
most bonding MO. The magic number for aromaticity in such arrays is just
the opposite as for a Huckel array, i.e., 4n pi systems are aromatic and 4n+2
systems are antiaromatic. So it can also be seen that the second cyclic array
in the favored path, which involves the doubly occupied sp2 AO of the
carbene, is a 4 electron Mobius array, which is aromatic. Consequently, the
favored path has two aromatic arrays and the disfavored one two
antiaromatic arrays.

Diels-Alder Cycloadditions. Perhaps the most famous, and also the most useful, of
all cycloaddition reactions is the Diels-Alder reaction of a dienophile with the s-
cis conformation of a conjugated diene. Again, the reaction is highly syn
stereospecific, both with respect to the dienophile and the diene. The stereospecific
reactions of diethyl maleate ( which has cis ester functions, E) and diethyl fumarate
(trans E’s) with 1,3-butadiene are depicted below (NP = nodal plane). In the specific
depictions, the dienophile is shown as approached the termini (C1 and C4) of the s-
cis conformation of the diene from above, so that the bottom lobes of the dienophile
orbitals overlap with the top lobes of the diene orbitals. The orbital signs suggested by
the light and dark lobes imply the interaction of the dienophile HOMO (which is
symmetric, like that of the BMO of ethene) with the LUMO of the conjugated diene
(this MO is also symmetrical and has two nodal planes, one between C1-C2 of the
diene and one between C3-C4 of the diene). Note also that the coefficients of the
diene LUMO are larger the termini (C1 and C4) than at the internal positions, as
implied by the sizes of the AO’s depicted. Most importantly, from the point of view
of FO theory, the interactions between both termini of the diene and the dienophile
are bonding, a circumstance which follows from the matched symmetrics of the
dienophile HOMO and the diene LUMO. The same favorable bonding situation is
found when examining the interactions of the diene HOMO and the dienophile
LUMO (try this as an exercise).

It is also of interest to note that for the cis dienophile there are two
diastereoisomeric transition states, both of which lead to the same cis Diels-Alder
adduct. The endo face of the TS is considered to be the one which lies directly (or
nearly directly) over the diene (especially C2 and C3), while the exo face is the one
which projects away from this diene moiety. In one cis TS both ester functions are
endo and in the other both ester functions are exo. In the single TS for the addition of
the trans dienophile, one ester function is endo and the other exo. We shall see
momentarily the reasons for the importance of recognizing the endo and exo faces of
a Diels-Alder transition state.

Not only is the addition to the dienophile syn stereospecific but, as the
drawing implies, it is also a syn stereospecific addition to the termini of the
conjugated diene, i.e., both new bonds to the dienophile are formed from the same
face, here shown to be the top face of the diene. The consequence of this
stereospecificity element is that different geometric isomers of the diene lead to
different adducts. For example, addition to E,E-2,4-hexadiene leads to adducts in
which the two methyl groups are cis to one another in the adduct, as shown below.
Again, the cis dienophile can orient the ester substitutents either endo or exo, but this
time the adducts are differentiated, and the endo one is slightly favored (more about
this later). The key points here are (1)the E methyl groups turn out to be cis to one
another in the adduct and (2) the majority endo product has the ester groups cis to the
methyl groups.

The illustration below indicates why the two E methyl substituents

end up being cis to one another and cis to the endo substituent (or endo H, as
the case may be). Specifically, the terminal carbons (C1 and C4) of the
conjugated diene rotate the E groups toward the face of the entering
dienophile and their Z groups away from that face in order to optimize
overlap with the dienophile pi orbitals. This is necessary because the
dienophile sits inside the perimeter of the diene system, so that the 2p lobes
on the same face as the dienophile must be rotated inward, toward the
dienophile pi system in order to maintain efficient overlap. The opposite
sense of rotation (shown in the bottom diagram) would not only result in
sharply diminished overlap between the diene termini and the dienophile pi
orbitals, but would introduce strong steric interactions between the Z groups
(even if these are only hydrogen) and the dienophile.

Stereochemistry of Beta Elimination Reactions

Elimination reactions are the reverse of additions, and it has previously been
noted that there are three potential stereochemical outcomes in additions, viz., anti
stereospecificity, syn stereospecificity, and nonstereospecificity. Not surprisingly, the
same three potential outcomes are possible in eliminations. In this case we are
speaking of the removal of two atoms or groups (normally a beta hydrogen and a
leaving group) from opposite faces of the developing pi bond, fromthe same face, or a
mixture of the two. When the elimination mechanism is a stepwise one (e.g., E1CB ),
the stereochemical result is usually nonstereospecificity. However, when the reaction
is concerted, as in the E2 elimination mechanism, the stereochemical preference is
typically anti stereospecificity. There appear to be two primary reasons for this
preference anti over syn stereospecificity. First, the anti elimination can proceed via a
TS in which eclipsing interactions are absent, whereas in the syn TS, eclipsing or
partial eclipsing occurs in the TS. A second possible reason, however, can be given in
terms of a HOMO/LUMO approach to the interaction of the developing carbanion
center at the beta carbon with the C-L bond involving the leaving group (L). Since the
carbanion center has a filled orbital, it must interact with a vacant C-L orbital if there
is to be a bonding interaction. Of course, that would be the antibonding MO
corresponding to the C-L bond. It has been noted that, ion contrast to the BMO, the
ABMO has an enlarged back lobe on carbon. This is the result of the interference
between the oppositely signed AO’s on carbon and the leaving group in the ABMO.
In effect, the orbital density is “chased” from the antibonding region onto the back
lobe. The enlarged back lobe then overlaps more efficiently with the carbanion orbital
than does the diminished front lobe.
A. Regioselectivity: It is often the case that addition and elimination reactions may,
in principle, proceed to more than one product. Thus 1-butene might add HBr to give
either 1-bromobutane or 2-bromobutane, depending on which carbon of the double
bond receives the hydrogen and which the bromine. If one possible product out of
two or more is formed preferentially, the reaction is said to be regioselective.

Simple substitution reactions are not normally considered regioselective, since by

definition only one constitutional product is possible. However, rearrangements are
known to occur during some reactions.

B. Stereoselectivity: If the reaction products are such that stereoisomers may be

formed, a reaction that yields one stereoisomer preferentially is said to be
stereoselective. In the addition of bromine to cyclohexene, for
example, cis and trans-1,2-dibromocyclohexane are both possible products of the
addition. Since the trans-isomer is the only isolated product, this reaction is
stereoselective.

C. Stereospecificity: This term is applied to cases in which stereoisomeric reactants

behave differently in a given reaction. Examples include:

(i) Formation of different stereoisomeric products, as in the reaction of

enantiomeric 2-bromobutane isomers with sodium methylthiolate, shown in
the following diagram.

Here, the (R)-reactant gives the configurationally inverted (S)-product, and

(S)-reactant produces (R)-product. The (R) and (S) notations for configuration
are described in a later section of this text.

(ii) Different rates of reaction, as in the base-induced elimination of cis &

trans-4-tert-butylcyclohexyl bromide (equation 1 below).

(iii) Different reaction paths leading to different products, as in the base-

induced elimination of cis & trans-2-methylcyclohexyl bromide (equation 2
below).