Stereoelectronic Effects in Organic Chemistry

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Classification of Solvents and Solvent Effects

Stereoelectronic effects guide the geometry and reactivity pattern of most of the ester functional groups. The importance of the stereoelectronic effects on the ester functional groups can be best understood by analyzing the role of these effects on the geometry and relative stability of two forms, Z and E forms of the ester group.

Fig 1.4

The Z form is more stable than E form by an amount of 3 kcal/mole. In case of tert-butyl formate the Z form predominates (90%) even if it suffers considerable steric interaction between the carbonyl oxygen atom and the bulky tert-butyl group. The reason behind this stability of Z form over E form is both primary and secondary stereoelectronic effects.

The primary electronic effect is due to the delocalization of electron between the ethereal oxygen and the carbonyl group which can be expressed by the following resonance structures:
Fig 1.4a

This can be viewed as n→π* interaction between the lone pair on ethereal oxygen and the π* orbital of the carbonyl group. As the esters are known to be planar and three atoms involved in delocalization are considered to be sp2 hybridized, the p orbitals are in the same plane and parallel to each other. So overlap can take place effectively in both the Z and E form of the ester function as shown in the diagram below (the lone pairs on O are omitted for clarity).
Fig 1.5a

The secondary electronic effects involves n→σ* interaction similar to anomeric effect. The carbonyl oxygen in both the Z and E esters has an electron pair orbital oriented antiperiplanar to the electron deficient C-OR bond so that n→σ* interaction can take place. In the Z form there is a possibility of another secondary electronic effect involving one lone pair on ethereal oxygen which is antiperiplanar to the C-O σ bond of the carbonyl group (as shown in the following diagram). This electron pair orbital can therefore overlap antibonding σ* orbital of that bond.
Fig 1.5b

So, in addition to primary electronic effect Z form has two secondary electronic effects whereas E form has one secondary electronic effect.

The additional stabilization energy in terms of secondary electronic effect in the Z form might be larger than that (=1.4 kcal/mole) observed in acetals because more polarized carbonyl bond lowers the energy of σ* orbital of the carbonyl group resulting in better overlap. So it is this extra secondary electronic effect which is responsible for the extra stabilization of Z form over E form.

The first interaction is called the primary interaction because it forms the conjugated system and it is energetically more important than the second one.

The importance of the secondary electronic effect is exemplified by the following study of SN2 displacement by iodide on lactonium salts.
Fig 1.6

The result is indeed quite surprising. In the process A, two molecules are formed (so entropically favorable) and the ring is not broken (so it follows the principle of least motion) while in process B only one molecule is formed and the ring is cleaved. Moreover, in lactonium salts having a methoxy group, the nucleophilic attack of iodide on the primary carbon centre (path A) should be more facile than attack on a secondary carbon centre (path B). So path A appears more favorable than path B. But the experimental observation belies this expectation. The reason behind this apparent anomalous result is stereoelectronic effect.

To understand what really goes on in here we need to investigate the events occurring at transition states. The transition states leading to the product of path A and B are illustrated by the following figures:
Fig 1.6a

In the TS leading to the product of path B, the electron pair orbital (the bond which is broken) which is generated on O upon the nucleophilic attack is antiperiplanar to the non polar C1-C2 bond whereas in the TS leading to product of path A, the electron pair orbital is antiperiplanar to the polar C1-O1 bond so that electron pair orbital can be delocalized by an interaction with the antibonding orbital (σ*) of the C1-O1 bond. This kind of delocalization is not possible for the TS leading to the product of path B. So the path A should be favored electronically over path B.

Now we will consider the formation and cleavage of the tetrahedral intermediates derived from esters.

According to the theory of stereoelectronic control for hydrolytic reactions, nucleophilic attack on esters must be perpendicular to the plane of the conjugated system and should give rise to a tetrahedral intermediate where the two oxygen atoms have each a lone pair oriented antiperiplanar to the newly formed bond. According to the principle of microscopic reversibility, the reverse process must follow the same path.

For example, a hemi-orthoester intermediate (1) which has two different alkoxy groups can give rise to two different esters (1a and 1b) and each having either a Z or E conformation.
Fig 1.6b

Theoretically intermediate 1 can have nine different gauche conformations as shown below.
Fig 1.6c

Conformers A and F are identical. Similarly conformers E and G; B and I are identical. Conformers A, B, and C represent the three possible conformers resulting from the attack of methoxide ion on a Z ester. Similarly, G, H and I are the three possible conformers resulting from the reaction of methoxide ion with an E ester. The predicted stereoelectronically controlled cleavage of each conformation of the hemi-orthoester is given in the table below. Conformer D cannot be cleaved as the requirement of two lone pair antiperiplanar to alkoxy group is not fulfilled.

Fig 1.6d


Mild acid hydrolysis of orthoester to the formation of ester proceeds through the formation of hemi-orthoester tetrahedral intermediate as shown in the following reaction scheme.

Let us consider a cyclic orthoester with two identical alkoxy groups. There are nine possible gauche conformations for this kind of cyclic orthoester.
Fig 7.1b

Out of these nine conformations, conformations B and D are high energetic due to steric interaction between two –R groups. So the population of these conformers at equilibrium is very low. The same is true for the conformers G, H and I where steric interaction between the –R group (of axial –OR) and the two methylene groups (C3 and C5) of the ring raises the energy of the conformers. Thus B, D, G, H and I- these conformers can be kept aside for the purpose of our discussion. Thus we presume that the hydrolysis proceeds through the energetically favored conformations i.e., A, C, E and F.

Conformers A and E can hydrolyze by the loss of axial alkoxy group as two antiperiplanar lone pair assist the cleavage of axial C-O bond (primary stereoelectronic effect). Conformer F can undergo a cleavage via the fission of the carbon-oxygen bond of the ring but the conformer C is unreactive as the condition of primary stereoelectronic effect is not satisfied. This prediction was experimentally verified with the following tricyclic orthoester (rigid model for conformer C) which is stable under mild acid condition.

Fig 7.1c

The reactivity of conformers A, E and F can now be understood in the light of secondary electronic effects.
Fig 7.1dd

All the three conformers can cleave the –OR bond with the help of primary electronic effects. But in the conformer A, the equatorial O has also an electron pair oriented antiperiplanar to the C-O bond of the ring. So, one secondary electronic effect will help the cleavage resulting ZZ lactonium ion. The same is true for the conformer F which yields EZ dialkoxy carbonium ion. But for conformer E ejection of axial –OR group is assisted by only primary stereoelectronic effects. So, on the basis of secondary stereoelectronic effects, cleavage of conformers A and F is preferred over that of E.

Between A and F, cleavage of conformer F is high energetic process since here only one molecule is formed (whereas cleavage of A generates two molecules and so entropically more favorable process) and the ring is broken (so it is not also assisted by the principle of least motion). In conclusion, we can say that the cyclic orthoester undergoes hydrolysis via conformer A only.

Now the ZZ lactonium ion undergoes stereoelectronically controlled (from the β face) nucleophilic attack by water yielding the tetrahedral intermediate which can have the following conformations:
Fig 7.1ee

Equilibrium between all the six conformers is only possible where the tetrahydropyran ring can easily undergo a chair inversion. Out of these 6 conformers, relative population of conformer 6 is negligible as this conformer has a strong steric interaction between the R group and the ring.

Now the conformer 2 cannot eject the alkoxy group as there is no primary stereoelectronic effect. It is therefore unreactive and must be eliminated from consideration.

Conformer 1 can yield a hydroxyl ester having a Z conformation whereas conformer 3 can produce a hydroxy ester having an E conformation. Lactone formation from 1-3 cannot take place with primary stereoelectronic control. Thus when the tetrahydropyran ring is conformationally rigid, then its hydrolysis must take place preferentially via conformer 1 yielding only the hydroxyl ester product in the Z conformation.

Intermediate 4 can either yield a Z (hydroxy-ester) or an E (lactone) ester. 5 can only yield an E lactone whereas intermediate 6 can produce two E esters - the hydroxyl ester and the lactone. So, primary stereoelectronic effects allow the formation of both the hydroxy ester and the lactone from conformers 4-6. However cleavage of 4 to yield a Z hydroxy ester is favored by one secondary stereoelectronic effect.

So it is predicted that hydrolysis of conformationally labile cyclic orthoester should produce hydroxy ester.

For example the following compounds give the corresponding hydroxy ester as the only product.

Fig 7.1f

But a mixture of hydroxy ester and lactone sometimes may be observed as the formation of hydroxy ester is not favored due to the reversibility of ring opening. If this factor becomes as important as secondary electronic effect then lactone formation can compete with hydroxy ester formation.

An acetal function can adopt any one of the nine gauche conformers described in Fig.1. below:
Fig 2.1

Conformers B, C, F are mirror images of the conformers D, G, H respectively. The remaining conformers A, E, I possess plane of symmetry. Hence there exist six different conformers. The relative stabilities of these conformers depend on stereoelectronic effects and the standard steric interactions.

Of these, conformer E and I are highly destabilized by the 1,3-diaxial interaction between the alkyl (R) groups and the Steric strain between the two OR groups respectively. According to the number of anomeric effects the stability is: F>B=C>A. A does not have any stabilization due to absence of Anomeric effect and also is destabilized by two butane-gauche interaction. B is stabilized by one anomeric effect and also has two gauche-butane interactions. C is stabilized by one anomeric effect and has one butane gauche interaction. F is stabilized by two anomeric effects and has one butane gauche interaction.


The anomeric effect or Edward-Lemieux effect is a stereoelectronic effect that describes the tendency of heteroatomic substituents adjacent to a heteroatom within a cyclohexane ring to prefer the axial orientation instead of the less sterically hindered equatorial orientation.

Fig 2.3


The destabizing electrostatic interaction between the lone pair of conformation B is high enough to force the molecule to adopt axial conformation A despite of the steric destabilization associated with it.
A is destabilized by 1,3-diaxial interaction between the C-O and two C-H bonds but is also stabilized by two anomeric effects. However, in B there is no anomeric effect and there exist the destabilizing interaction between the lone pairs of two oxygens. Experimentally, the conformer A has lower energy.


Fig 2.4b

For anomeric effect to operate, polarized C-X bond must be antiperiplanar to the lone pairs.

A nice evaluation of the anomeric effect is found in the acid catalyzed isomerisation of the cis and trans bicyclic acetals 1 and 2. At equilibrium, the mixture contained 57% cis isomer and 43% trans isomer at 80 °C which suggests that the cis isomer is more stable than the trans isomer by 0.17 Kcal/mol.
Fig 2.4c

The cis isomer (1) has one stabilizing interaction by anomeric effect while the trans isomer (2) has none. Steric interaction makes the cis acetal more energetic than the trans acetal by approximately 1.65 Kcal/mol (one butane gauche interaction of 0.85 Kcal/mol and an OR group axially to cyclohexane of 0.8 Kcal/mol). Thus at a first glance the stabilization of cis isomer caused by anomeric effect is expected to be 1.82 Kcal/mol (1.65 Kcal/mol + 0.17 Kcal/mol). However entropy factor favors cis isomer as cis acetal exist as a mixture of two conformers by ring flip while trans acetal is locked in a single conformer. This reduces the energy of cis isomer by 0.42 Kcal/mol. Thus the entropy corrected stabilization conferred by anomeric effect on the cis isomer is 1.4 Kcal/mol.

Stabilization by anomeric effect is further elucidated as we study 1,7-dioxaspiro[5.5]undecane.
Fig 2.4d

3A: 2 Anomeric effect - stabilization by 2 × 1.4 = 2.8 Kcal/mol, destabilization by two axial OR groups: 2 × 0.8 = 1.6 Kcal/mol. Net stabilization: 1.2 Kcal/mol.

3B: 1 Anomeric effect - stabilization by 1.4 Kcal/mol, destabilization by one OR group: 0.8 Kcal/mol and destabilization by one CH2 group by 1.8 Kcal/mol; Net destabilization: 1.2 Kcal/mol.

3C: No anomeric effect stabilization. Destabilisation by two CH2 group: 2 × 1.8 = 3.6 Kcal/mol which is the net destabilization.

Hence, the conformer 3A is more stable than conformer 3B by 2.4 Kcal/mol and 3C by 4.8 Kcal/mol. Thus, this analysis predicts that the spiro compound essentially exists in conformation 3A and this is supported by 13C NMR studies.

The spiro compound having two methyl groups is studied. From the isomers of dl-dihydroxyketone (4A) and meso-dihydroxyketone (4B), acid catalyzed cyclization gives three possible isomers-two of them (5A and 5B) from cyclization of 4A and one isomer (5C) obtained from cyclization of 4B.
Fig 2.4e

File:fig2.5.pngFig 2.5

Under acidic condition, 5A and 5B are readily interconvertible and under strong acidic condition that allows epimerization of 4A and 4B, all three 5A, 5B and 5C are interconvertible. Molecular model shows that 5A and 5B can exist in three different conformers while four different conformers are possible for 5C. Analysis of Steric and stereoelectronic effects of different conformers indicated that isomer 5A exist only as 6A (0 Kcal/mol) and isomer 5B exist only as isomer 6B (1.8 Kcal/mol) while isomer 5C exist as a mixture of major (6C, 3.1 Kcal/mol) and minor (6D, 3.7 Kcal/mol) conformers.

Fig 2.5a

6A is thus energetically the most favorable conformation as it has stabilization by two anomeric effects. The two methyl groups are also in the equatorial position, thus the 1,3- diaxial interaction is absent. However, in 6B, the two methyl groups are in the axial position, leading to the 1,3- diaxial interactions. So, 6B has more energy than 6A though both have two anomeric effects.

In case of the following spiro compound (7), anomeric effect is effective only if the central ring is twist boat (7A). Here two anomeric effects operate.
Fig 2.5b


Fig 2.6

Fig 2.6a

In conformer C, cleavage occurs very fast as it is stabilized by one anomeric effect.

Fig 2.6b

In conformer F, cleavage is not that feasible as C-O bond to be cleaved has double bond character due to two anomeric effects.
Fig 2.6c

Hence, rate of hydrolysis: Conformer C undergoes fastest hydrolysis followed by F and the least rate of hydrolysis is shown by A.

The fact that the rate of hydrolysis is controlled by the stereoelectronic effect is proved by considering the tricyclic acetal systems which has the disposition of lone pairs as in conformer A and C described before. The rate of acid catalysed hydrolysis (0.1 N HCl) of tricyclic acetal (9) which has no electron pair antiperiplanar to the leaving group and 9A which has an electron pair properly oriented to eject the leaving group is studied. It is found that 9A hydrolyse about 3000 times faster than 9.

Fig 2.6d

In the study of acetal cleavage of axially oriented p-nitrophenoxy acetals 10 and 10A, loss of p-nitrophenolate from these compounds would generate the oxonium ion 11, an acetal with a good leaving group as aldehyde oxygen. If one of the electron pairs on the oxygen atom of ring A in 11 is in a position to participate, it should trigger a concerted reaction to form 11A directly. Such participation of the lone pair is possible only in case of the cis isomer 10A. So, the rate of hydrolysis of trans isomer 10 is much slower.

Fig 2.6e

In case of acetal formation and cleavage, both the attack of the nucleophile and the release of ROH is subject to stereoelectronic effect. Attack of nucleophile to electrophile must restore the lone pair disposition to have anomeric effect.

Fig 2.6f


Fig 2.6g


Fig 2.6h

It is found that upon hydride removal, if formation of carbocation is assisted by two lone pairs positioned appropriately, then reaction is faster. A high primary kinetic effect (kH/kD) is observed. Also, from mechanism 1 and 2, the need for electron pair antiperiplanar to the C-H bond for each oxygen atom becomes clear. The radical mechanism is also possible as radical would be more stable when there are two lone pairs on adjacent oxygen oriented antiperiplanar to it. Hence oxidation of C-H bond of acetal by ozone is faster in 12 than in 12A.

Fig 2.6i

In case of diaryl ketone, the triplet state also behaves like a radical.
Fig 2.6j

Triplet benzophenone abstracted axial hydrogen from cis-2-methoxy-4-methyltetrahydropyran (13) about 8 times faster than it abstracted equatorial hydrogen from trans isomer (13A).
Fig 2.6k

Fig 2.7

As shown below, both the reactions seem reasonable as both the reactions lead to the formation of strain free 5 membered rings. However, in practice, the first reaction has been found not to occur though the lactum has been found to be formed in the second reaction.

Fig 2.7a

This example immediately gives insinuation to the fact that some cyclizations are favored over others. Baldwin summarized those cyclization rules in different systems and is known as Baldwin’s Rules. These are more empirical observations backed up by some sound stereoelectronic reasoning.

Before going into the details, let us first introduce the nomenclatures used in different cyclizations as proposed by Baldwin. General form of nomenclature for any cyclization reaction is:
Fig 2.7b

Where, numerical prefix denotes the ring size being formed; endo or exo is used depending upon whether the bond that breaks as the ring forms is inside (endo) or outside (exo) the new ring; tet, trig and dig are used when the electrophile is an sp3 (tetrahedral), sp2 (trigonal) and sp (diagonal) respectively. Let us illustrate this with pictorial examples:

Fig 2.7c


Fig 2.7d..

The rules can be understood by the following orbital picture:

Fig 2.7d...

In exo-tet cyclizations the lone pair on X and the C-Y σ* can overlap successfully irrespective of bond size. In all cases, the attack occurs 1800 away with respect to the leaving group. However, in case of 5- and 6- endo tet cyclizatios this type of overlap is not possible due to unfavorable orientations of the orbitals involved. So, 5- and 6- endo-tet cyclizations are disfavored.

Let us consider few examples:

Fig 2.7e.

In both the cases the exo trig cyclization is preferred in accordance with Baldwin’s rules.

The famous example of application of Baldwin’s rules for tetrahedral system is the following:

Fig 2.7f

At a first glance, the reaction product compels us to think a reaction mechanism as outlined above. Thus, as an intermediate step, we are invoking 6-endo-tet cyclization which according to Baldwin’s rule is not allowed. This mechanism also seems right in light of the fact that intramolecular reactions are extremely favorable. In spite of its appeal, Eschenmoser first showed that the mechanism is wrong. He believed that the reaction is intramolecular and Baldwin’s rule is still obeyed here. To prove his hypothesis, he performed a cross-over experiment. He mixed together the starting material for the reaction above with the hexadeuterated compound shown below, and re-ran the reaction. If the reaction had been intramolecular, then product would have contained either six deuteriums, or no deuterium. In the experiment, he observed formation of 25% hexadeuterated, 25% undeuterated and 50% trideuterated compound. The result is consistent with the intermolecular reaction as shown below:

Fig 2.7g


Fig 2.7g..

The rules can be understood by the following orbital picture:

Fig 2.7h

Here also the nucleophilic lone pair can overlap with the π* of the double bond to form a new bond following Burgii-Dunitz trajectory (i.e. attack at 109° angle). However, for 3-, 4-, and 5- endo-trig cyclization reactions we have following orbital pictures:
Fig 2.7h..

As may be seen in the first orbital picture, though the lone pair is nearby to the methylene carbon, it is almost orthogonal to the π*orbital. This improper alignment prevents the overlap. In the second picture, however, the lone pair is in the same plane of the π*orbital; but it moves too far away to overlap effectively.File:2.7i..png

Fig 2.7i..

To carry out the above conversion one would immediately think of base-catalyzed intramolecular Michael addition. However, it would not lead to the formation of the desired product because 5-endo-trig cyclization is not allowed.

Fig 2.7j.

However, the same product can be achieved if we try to carry out the reaction in presence of catalytic amount of acid. The reaction course completely changes and a 5-exo-trig cyclization leads to the formation of the product.

Fig 2.7k.


Fig 2.7l.


Fig 2.7m.

The origin of the rules can be understood in terms of the following orbital picture:

Fig 2.7m..

As the alkyne has two mutually orthogonal π*orbitals, one of them must always be in plane of the new ring, making it much easier for the nucleophile to access. But, for 3- and 4- exo-dig cyclizations this is highly improbable since the lone pair cannot access any of the π*orbitals.


Fig 2.7o.


Fig 2.7p.


Baldwin’s rules are only guidelines for the reaction kinetics. It should be re-emphasized that it works only when reactions follow kinetic pathway. However, if the thermodynamic stability of the product becomes too heavy to ignore, then Baldwin’s rule can be outweighed. The most famous example is probably the acetal formation from a carbonyl compound.File:2.7r.png

Fig 2.7r.

The 5-endo-trig cyclization step which is not predicted by Baldwin’s rule occurs here driven by the thermodynamic stability of the product acetal!

Again pericyclic reactions are completely different class of reactions and consequently they are not bound by Baldwin’s rules.

When a second row element in the periodic table is incorporated in the ring being formed then Baldwin’s rule may not work.

Fig 2.7s

Here, the C-S bond being long can access the π* orbital of the double bond. Also the vacant d-orbital of S atom can initiate the interaction. As a sequel, the 5-endo-trig cyclization occurs simultaneously with the 5-exo-trig cyclization.


Fig 2.7t

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