Conformational isomerism
Encyclopedia
In chemistry
, conformational isomerism is a form of stereoisomerism
in which the isomer
s can be interconverted exclusively by rotations about formally single bonds. Such isomers are generally referred to as conformational isomers or conformers and specifically as rotamers when the rotation leading to different conformations is restricted (hindered) rotation,in the sense that there exists a rotational energy barrier that needs to be overcome to convert one conformer to another. Conformational isomers are thus distinct from the other classes of stereoisomers for which interconversion necessarily involves breaking and reforming of chemical bonds. The rotational barrier, or barrier to rotation, is the activation energy
required to interconvert rotamers.
ic and an anti conformer, where the four carbon centres are coplanar. The three eclipsed conformations with dihedral angle
s of 0°,120° and 240° are not considered to be rotamers, but are instead transition states.
Some important examples of conformational isomerism include:
The population of different conformers follows a Boltzmann distribution
:
The left hand side is the equilibrium ratio of conformer i to the total.
is the relative energy of the i-th conformer from the minimum energy conformer. 
is the relative energy of the k-th conformer from the minimum energy conformer. R is the molar ideal gas constant equal to 8.31 J/(mol·K) and T is the temperature in kelvin
s (K). The denominator of the right side is the partition function.
The dynamics of conformational (and other kinds of) isomerism can be monitored by NMR
spectroscopy at varying temperatures. The technique applies to barriers of 8-14 kcal/mol, and species exhibiting such dynamics are often called "fluxional".
Reaction rates are highly dependent on the conformation of the reactants. This theme is especially well elucidated in organic chemistry. One example is provided by the elimination reaction
s, which involve the simultaneous removal of a proton and a leaving group
from vicinal positions under the influence of a base. The mechanism requires that the departing atoms or groups follow antiparallel trajectories. For open chain substrates this geometric prerequisite is met by at least one of the three staggered conformers. For some cyclic substrates, however, an antiparallel arrangement may not be attainable depending. Adjacent substituent
s on a cyclohexane ring can achieve antiperiplanarity only when they occupy trans diaxial positions. One consequence of this analysis is that trans-4-tert-butylcyclohexyl chloride cannot easily eliminate but instead undergoes substitution.
Side-chain dihedral angles are not evenly distributed, but for most side chain types, the
angles occur in tight clusters around certain values. Rotamer libraries therefore are usually derived from statistical analysis of side-chain conformations in known structures of proteins by clustering observed conformations or by dividing dihedral angle space into bins, and determining an average conformation in each bin. This division is usually on physical-chemical grounds, as in the divisions for rotation about sp3-sp3 bonds into three 120° bins centered on each staggered conformation (60°, 180°, -60°).
Rotamer libraries can be backbone-independent, secondary-structure-dependent, or backbone-dependent. The distinctions are made depending on whether the dihedral angles for the rotamers and/or their frequencies depend on the local backbone conformation or not. Backbone-independent rotamer libraries make no reference to backbone conformation, and are calculated from all available side chains of a certain type. Secondary-structure-dependent libraries present different dihedral angles and/or rotamer frequencies for
-helix, 
-sheet, or coil secondary structures. Backbone-dependent rotamer libraries present conformations and/or frequencies dependent on the local backbone conformation as defined by the backbone dihedral angles 
and 
, regardless of secondary structure. Finally, a variant on backbone-dependent rotamer libraries exists in the form of position-specific rotamers, those defined by a fragment usually of 5 amino acids in length, where the central residue’s side chain conformation is examined.
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....
, conformational isomerism is a form of stereoisomerism
Stereoisomerism
Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms , but that differ only in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but the bond connections...
in which the isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
s can be interconverted exclusively by rotations about formally single bonds. Such isomers are generally referred to as conformational isomers or conformers and specifically as rotamers when the rotation leading to different conformations is restricted (hindered) rotation,in the sense that there exists a rotational energy barrier that needs to be overcome to convert one conformer to another. Conformational isomers are thus distinct from the other classes of stereoisomers for which interconversion necessarily involves breaking and reforming of chemical bonds. The rotational barrier, or barrier to rotation, is the activation energy
Activation energy
In chemistry, activation energy is a term introduced in 1889 by the Swedish scientist Svante Arrhenius that is defined as the energy that must be overcome in order for a chemical reaction to occur. Activation energy may also be defined as the minimum energy required to start a chemical reaction...
required to interconvert rotamers.
Types of conformational isomerism
Butane has three rotamers: two gauche conformers, which are enantiomerEnantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
ic and an anti conformer, where the four carbon centres are coplanar. The three eclipsed conformations with dihedral angle
Dihedral angle
In geometry, a dihedral or torsion angle is the angle between two planes.The dihedral angle of two planes can be seen by looking at the planes "edge on", i.e., along their line of intersection...
s of 0°,120° and 240° are not considered to be rotamers, but are instead transition states.
Some important examples of conformational isomerism include:
- Linear alkane conformations with staggered, eclipsed and gauche conformers, and
- Ring conformation
- Cyclohexane conformationCyclohexane conformationA cyclohexane conformation is any of several three-dimensional shapes that a cyclohexane molecule can assume while maintaining the integrity of its chemical bonds....
s with chair and boat conformers. - Carbohydrate conformationCarbohydrate conformationCarbohydrate conformation is the characteristic 3-dimensional shape of a carbohydrate. Conformations of monosaccharide and oligosaccharide heavily influence their reactivity and recognition by other molecules, which are essential to mammals and other organisms....
- Cyclohexane conformation
- Atropisomerism- due to restricted rotation about a bond, a molecule can become chiral
- FoldingFolding (chemistry)In chemistry, folding is the process by which a molecule assumes its shape or conformation. The process can also be described as intramolecular self-assembly where the molecule is directed to form a specific shape through noncovalent interactions, such as hydrogen bonding, metal coordination,...
of molecules, where some shapes are stable and functional, but others are not.
Equilibrium population of conformers
Boltzmann distribution
In chemistry, physics, and mathematics, the Boltzmann distribution is a certain distribution function or probability measure for the distribution of the states of a system. It underpins the concept of the canonical ensemble, providing its underlying distribution...
:
The left hand side is the equilibrium ratio of conformer i to the total.
is the relative energy of the i-th conformer from the minimum energy conformer. is the relative energy of the k-th conformer from the minimum energy conformer. R is the molar ideal gas constant equal to 8.31 J/(mol·K) and T is the temperature in kelvinKelvin
The kelvin is a unit of measurement for temperature. It is one of the seven base units in the International System of Units and is assigned the unit symbol K. The Kelvin scale is an absolute, thermodynamic temperature scale using as its null point absolute zero, the temperature at which all...
s (K). The denominator of the right side is the partition function.
Isolation or observation of the conformational isomers
- Atropoisomers can be quite stable depending on the steric effects and were the first conformational isomers to be identified. In the biphenylBiphenylBiphenyl is an organic compound that forms colorless crystals. It has a distinctively pleasant smell. Biphenyl is an aromatic hydrocarbon with a molecular formula 2...
ic system atropisomerism is especially prevalent, e.g. binaphthol1,1'-Bi-2-naphthol1,1'-Bi-2-naphthol is an organic compound that is often used as a ligand for transition-metal catalysed asymmetric synthesis. BINOL has axial chirality and the two enantiomers can be readily separated and are stable toward racemisation. The specific rotation of the two enantiomers is +/- 35.5°...
. - In cyclohexane derivativesCyclohexaneCyclohexane is a cycloalkane with the molecular formula C6H12. Cyclohexane is used as a nonpolar solvent for the chemical industry, and also as a raw material for the industrial production of adipic acid and caprolactam, both of which being intermediates used in the production of nylon...
, the two chair conformers interconvert with rates on the order of 105ring flips/sec, which obviously precludes their separation. The equatorial conformer crystallizes selectively, and when these crystals are dissolved at very low temperatures, one can directly monitor the approach to equilibrium by NMR spectroscopy.
Techniques for study of conformational isomerism
Most information on conformational isomerism comes from single crystal X-ray diffraction studies. IR spectroscopy is ordinarily used to measure conformer ratios. For the axial and equatorial conformer of bromocyclohexane, νCBr differs by almost 50 cm−1.The dynamics of conformational (and other kinds of) isomerism can be monitored by NMR
NMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 NMR...
spectroscopy at varying temperatures. The technique applies to barriers of 8-14 kcal/mol, and species exhibiting such dynamics are often called "fluxional".
Conformation-dependent reactions
Elimination reaction
An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a one or two-step mechanism...
s, which involve the simultaneous removal of a proton and a leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
from vicinal positions under the influence of a base. The mechanism requires that the departing atoms or groups follow antiparallel trajectories. For open chain substrates this geometric prerequisite is met by at least one of the three staggered conformers. For some cyclic substrates, however, an antiparallel arrangement may not be attainable depending. Adjacent substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
s on a cyclohexane ring can achieve antiperiplanarity only when they occupy trans diaxial positions. One consequence of this analysis is that trans-4-tert-butylcyclohexyl chloride cannot easily eliminate but instead undergoes substitution.
Protein rotamer libraries
A rotamer library is a collection of rotamers for each residue type in proteins with side-chain degrees of freedom. Rotamer libraries usually contain information about both conformation and frequency of a certain conformation. Often libraries will also contain information about the variance about dihedral angle means or modes, which can be used in sampling.Side-chain dihedral angles are not evenly distributed, but for most side chain types, the
angles occur in tight clusters around certain values. Rotamer libraries therefore are usually derived from statistical analysis of side-chain conformations in known structures of proteins by clustering observed conformations or by dividing dihedral angle space into bins, and determining an average conformation in each bin. This division is usually on physical-chemical grounds, as in the divisions for rotation about sp3-sp3 bonds into three 120° bins centered on each staggered conformation (60°, 180°, -60°).Rotamer libraries can be backbone-independent, secondary-structure-dependent, or backbone-dependent. The distinctions are made depending on whether the dihedral angles for the rotamers and/or their frequencies depend on the local backbone conformation or not. Backbone-independent rotamer libraries make no reference to backbone conformation, and are calculated from all available side chains of a certain type. Secondary-structure-dependent libraries present different dihedral angles and/or rotamer frequencies for
-helix, -sheet, or coil secondary structures. Backbone-dependent rotamer libraries present conformations and/or frequencies dependent on the local backbone conformation as defined by the backbone dihedral angles and , regardless of secondary structure. Finally, a variant on backbone-dependent rotamer libraries exists in the form of position-specific rotamers, those defined by a fragment usually of 5 amino acids in length, where the central residue’s side chain conformation is examined.See also
- IsomerIsomerIn chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
- Steric effectsSteric effectsSteric effects arise from the fact that each atom within a molecule occupies a certain amount of space. If atoms are brought too close together, there is an associated cost in energy due to overlapping electron clouds , and this may affect the molecule's preferred shape and reactivity.-Steric...
- Molecular configurationMolecular configurationThe configuration of a molecule is the permanent geometry that results from the spatial arrangement of its bonds. The ability of the same set of atoms to form two or more molecules with different configurations is stereoisomerism...
- Macrocyclic StereocontrolMacrocyclic StereocontrolMacrocyclic stereocontrol refers to the directed outcome of a given inter or intramolecular reaction on a ring containing 8 or more atoms that is governed by the conformational or geometrical preference of the ring rather than by remote or absolute stereochemical methods...