Swetha Satheesh V

Introduction
In heterocyclic compounds, the existence of ring system imposes constraints on the molecule
which may be absent in acyclic systems. Flexible molecules preferentially adopt
conformations in which the bonding interactions are maximised and non-bonding
interactions are minimised. Ring inversion refers to the process by which the molecule
undergoes a conformational change, causing the ring to invert or flip inside out. This
behaviour is of paramount importance in various fields of chemistry, including organic
synthesis, drug design, and materials science. However, ring inversion is not always a smooth,
unhindered process. There occurs some barrier energy to ring inversion due to the nature of
heteroatoms and size of the ring.
Pyramidal inversion plays a pivotal role in stereochemistry, molecular chirality, and reaction
mechanisms, profoundly impacting the properties and behaviour of various organic
compounds. Understanding the principles behind pyramidal inversion is crucial for predicting
and elucidating molecular behaviour, designing efficient synthetic strategies, and unravelling
the intricacies of complex chemical reactions.
1,3-diaxial interaction refers to the unfavourable steric interaction that occurs between two
groups situated on the same side of a cyclohexane ring, separated by three carbon atoms.
This proximity creates a clash between the bulky substituents, resulting in destabilization and
increased energy of the molecule.

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Barrier to Ring Inversion
Saturated heterocycles contain carbon-heteroatom bonds and, in some cases, heteroatom-
heteroatom bonds, as part of the ring system. The barriers to rotation about these bonds are
different from those about carbon-carbon bonds.
 Single bonds between carbon and heteroatom have a lower barrier to rotation than
for carbon-carbon bonds.
 On the other hand, heteroatom-heteroatom bonds have a much higher barrier to
rotation than carbon-carbon bonds.

Compound Rotational barrier

[kcal/mol (kJ/mol)]
CH3-CH3 2.9 (12.2)
CH3-NH2 2.0 (8.3)
CH3-OH 1.1 (4.6)
CH3-SH 1.3 (5.3)

Table 1| Rotational energy barriers for single bonds

The chair conformation adopted by the cyclohexane and its derivatives are also preferred
ones for six-membered heterocycles.

Fig 1|Ring inversion in six membered heterocycles.

The conformational energy barrier to ring inversion in tetrahydropyran is similar to that in

cyclohexane.

X ΔG T (˚C)
[kcal/mol(kJ/mol)]
O 9.9 (41.4) -65
NH 10.4 (43.5) -62.5
S 9.0 (37.6) -93
Where ΔG is the energy barrier to ring inversion at T˚C temperature.
Table 2|Barriers to ring inversion in six membered heterocycles

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In ring inversion, the axial substituents are converted into equatorial and vice versa.

Fig 2| Ring Inversion in six-membered heterocycles

Cyclobutane is a puckered molecule with a barrier to ring puckering of 1.5kcal/mol

(6.3kJ/mol). The barrier is slightly lower in azetidine [1.3 kcal/mol (5.4kJ/mol)] and the two
conformers are unequal in energy, that having the NH bond equatorial being the more stable
(fig 3).

Fig 3| Ring puckering in azetidine

In the corresponding four-membered oxygen heterocycle, oxetane, the energy barrier to

puckering is lower than the ground vibrational energy level, so the molecule is essentially
planar and freely vibrating.
Simple five membered ring heterocycles can be represented as a series of freely
interconverting non-planar structures, such as the envelop form and the half chair form (fig4).

Fig 4| a envelop form and b half chair form of five membered heterocycles

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Pyramidal Inversion
Pyramidal inversion is a property of nitrogen which distinguishes it from the tetravalent
carbon.
 It occurs when the lone pair on nitrogen oscillates from one side of the plane of the
three atoms attached to it to the other side of that plane. Lone pair is constantly
moving from one side of the nitrogen atom to the other side and it goes through a
transition state.
In amine, hydrogens and the substituents are in one plane and lone pair is in a p orbital.

In ammonia and amines, the bonds to nitrogen are pyramidal with bond angles closer to the
tetrahedral value of 109.5˚ -109.5˚ than to the 90˚-90˚ value expected for the use of pure p-p
orbitals of nitrogen in bond formation. We consider that the nitrogen in amines is formulated
best with hybrid orbitals; three of these orbitals are used in σ-σ bond formation while the
fourth contains the nonbonding electron pair:

The trivalent nitrogen in a flexible ring inserts another conformational property to the ring.
Hydrogen or a substituent at the nitrogen atom in a ring can attain two equilibrating
configurations by virtue of inversion of the nitrogen atom. Many molecules could invert, but
in the case of nitrogen is barrier to inversion low enough for inversion to occur at an
observable rate. Rapid lone pair tunnelling and inversion is unique to nitrogen.

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Other elements with one or more lone pairs, such as phosphorous or sulfur, either invert only
very slowly or not at all.
The rate of atomic inversion is affected by the size of the ring in which nitrogen is inserted
and the substituent(s) attached to nitrogen.

When nitrogen atom is involved in three-membered ring i.e., aziridine, the conformational
changes arise mainly from the pyramidal inversion of nitrogen because the aziridine ring is
planar and rigid.
The pyramidal inversion in aziridine is reduced because of much higher energy barrier in
aziridine (ΔG*=72.0 kJ/mol) as compared to the energy barrier in acyclic unstrained
compounds which have very low energy barrier (NH3 = 24-25 kJ/mol and (CH3)3N = 34.4
kJ/mol).

 This is due to the increased angle strain in the planar transition state required for
inversion.
 The bond angle in aziridine differs from the normal tetrahedral angle by about 50˚, the
angle in planar transition state deviates from that in unsaturated planar nitrogen by
60˚; thus, there is increased angle strain in the transition state and an increased barrier
to inversion.

The energy barrier to pyramidal inversion in aziridines depends on the nature of the
substituent attached to the nitrogen atom;
 Electron delocalizing substituents on small ring nitrogen lower the inversion barrier by
lowering the energy of the transitional 'flat' geometry in which three substituents of
nitrogen are in the same plane.
 The substituents bearing unshared electron pairs (NH2, CI, OCR3) increase the energy
barrier considerably and the enantiomers can be isolated. (The increased energy barrier
is probably due to the unfavourable lone pair-lone pair interactions in the planar
transition state.)

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The N inversion barrier is lowered by conjugation with π-electron withdrawing groups, which
stabilise the transition state (in which the N lone-pair is in a pure 2p orbital) by delocalisation.

 The solvents which stabilize ground state conformer through the hydrogen bonding or by
solvation raise the energy barrier.

If the nitrogen atom is part of a three-membered ring (aziridine) or a four-membered ring

(azetidine) inversion is significantly retarded by strain.
However, the angle strain on the pyramidal inversion in azetidine is much smaller than in
aziridines; for azetidine ΔG=7.2kcal/mol (30 kJ/mol) at -119˚C.

The situation is similar (although somewhat less severe) in an azetidine. In larger rings, such
as a pyrrolidine ring or a piperidine ring, the strain increase required for inversion is less.
Inversion can occur, and these are non-resolvable because the barrier to ring inversion is low.
Therefore, the rate of interconversion will be large as compared to aziridine.

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 R ΔG
[kcal/mol(kJ/mol)]
H 17.3(72)
Et 19.4(81)
CMe3 17(71)
Ph 11.7(49)
SO2Me 12.8(53.5)
CONMe2 9.9(41)
NH2 >22(>90)
Cl >21(>90)
OMe >22(>90)

Table 3|Influence of nitrogen substituents on barriers to nitrogen inversion (ΔG) in aziridines

 Conjugatively electron withdrawing substituents, which stabilize the planar transition

state, lower the energy barrier.
 There may also be steric effect that destabilizes the pyramidal forms, as illustrated by
the lower barrier for the t-butyl derivatives.
 Inductively electron withdrawing groups with an adjacent lone pair raises the barrier
considerably.

Fig 8|Conformational changes in piperidine. Process A and B involve pyramidal inversion, C

and D are ring inversions.

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1,3- Diaxial Interaction
A 1,3-diaxial interaction refers to the steric interactions that occur between paired electrons
in the syn-axial position. These interactions typically involve repulsion and are observed in
six-membered homocycles (such as cyclohexane and its derivatives) and heterocycles when
they adopt an axial chair conformation.

a. 1,3-Diaxial Interactions Six Membered Homocycles

1,3-Diaxial interactions are steric interactions between an axial substituent located
on carbon atom 1 of a cyclohexane ring and the hydrogen atoms (or other
substituents) located on carbon atoms 3 and 5.

For Example, Consider the axial form of methyl cyclohexane

 The methyl group are above or below the plane of cyclohexane ring. i.e, axial position.
 The methyl group will interact with the two hydrogens also in the axial positions and
facing the same direction.
 The MOs of these groups interfere with each other which in turn makes this
conformation high in energy and unfavourable.

Fig 9| 1,3-diaxial interaction in methylcyclohexane

b. 1,3 Diaxial Interactions Six Membered Heterocycles

Six-membered heterocycles have increased 1,3- diaxial interaction compared to
cyclohexane ring due to shorter bond length.

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 Fig 10|Ring inversion in 2-methyl-1,3-dioxane and 5-methyl-1,3-dioxane
In 2-methyl-1,3-dioxane, the conformation a (fig 10) with an equatorial methyl group is even
more favoured than in methylcyclohexane [ΔG=4 kcal/mol] at 25˚C because shorter C-O
bonds cause larger 1,3-diaxial interactions in b than in methylcyclohexane.
On the other hand, c is only slightly preferred over d because in the axial conformer d, the
interactions of methyl group with the lone pairs on oxygen are much smaller than the 1,3-
diaxial interactions with CH bonds which occur in axial methyl cyclohexane.
It is even possible for bulky alkyl groups such as t-butyl to occupy the 5-position as axial
substituents.

Anomeric effect
Electronegative 2-substituents on tetrahydropyrans often show a preference for axial
positions even though this is sterically hindered: this preference, which is called the anomeric
effect. The conformational preference was first recognized in carbohydrate chemistry, many
sugars having pyranose ring structures with oxygen substituents at the 2- position.
It became known as the anomeric effect because it was found in anomeric equilibria between
α- and β-glycosides.

2-Substituent Anomeric effect

[kcal/mol (kJ/mol)]
Cl 2.4 (10.0)
Br 2.3 (9.6)
OMe 1.7 (7.1)
SMe 1.5 (6.3)
OH 0.8 (3.3)
NHMe 0.4 (1.7)

Table 4| Anomeric effect for 2-substituents in tetrahydropyrans

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The values for the anomeric effect show that the values increase with the inductively electron
withdrawing character of the substituent. The values are not large and the equilibrium
position is influenced by the presence of other ring substituents (fig 11) and by solvent effects.
 The proportion of axial conformer in solution decreases as the dielectric constant of
the solvent increases because the equatorial conformers are more polar.
 Strongly hydrogen-bonding solvents also preferentially stabilize conformers with
equatorial alkoxy groups.

Fig 11|The anomeric effect for 2-methoxytetrahydropyran and the influence of a 4-methyl
substituent on the position of equilibrium
 The anomeric effect is not obviously present in piperidines and other six membered
nitrogen heterocycles. However, it seems that the anomeric effect does exist in
these compounds but is masked by steric interactions between the substituents at C-
2 and at nitrogen.
The anomeric effect was explained in terms of electrostatic interactions. In the equatorial
conformer (fig 12a) of a 2-substituted tetrahydropyran the dipoles due to the
electronegative atoms are aligned and there should be a repulsive interaction, whereas in
the axial conformer, the dipoles are opposed; thus, the axial conformer should be favoured.

Fig 12|Alignment of dipoles in equatorial and axial conformations of tetrahydropyran

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Conclusion
Barrier to ring inversion, the energy required to ring inversion changes with heteroatoms in
heterocycles. Also, it changes with the number of atoms in the heterocylic rings. Generally,
the barrier to ring inversion decreases with the increase in size of the heterocycle.
Pyramidal inversion is a rapid oscillation of the nitrogen atom and substituents, the nitrogen
atom passes through the plane formed by the substituents. Pyramidal inversion in three
membered heterocycle (aziridine) is much slow because of the high barrier to ring inversion
arises due to the strain associated with the three membered ring.
1,3-diaxial interaction is another steric interaction arises due to the repulsive interaction
between the axial substituents and axial hydrogens in 1,3 positions of a heterocyclic
compound.

References
 Gilchrist T L, Heterocyclic Chemistry. 3rd Edition. (Pearson Education India, 2005).
 Nasipuri, D. Stereochemistry of Organic Compounds: Principles and Applications. (New
Age International, 1994).

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