As defined in an earlier section, isomers are different compounds that have the same molecular formula. When the group of atoms that make up the molecules of different isomers are bonded together in fundamentally different ways, we refer to such compounds as constitutional isomers. For example, the C4H8 alkenes 1-butene, CH2=CHCH2CH3, and 2-methylpropene, (CH3)2C=CH2, are constitutional isomers. However, we find that the remaining isomeric alkene, 2-butene, exists as two isomers, designated cis and trans. Physical properties for all four isomers are given in the following table.
In order to understand how two stable isomers of 2-butene can exist, it is necessary to consider how the double bond substituents are oriented in space. The carbon-carbon double bond is formed between two sp2 hybridized carbons, and consists of two occupied molecular orbitals, a sigma orbital and a pi orbital. Rotation of the end groups of a double bond relative to each other destroys the p-orbital overlap that creates the pi orbital or bond. Because the pi bond has a bond energy of roughly 60 kcal/mole, this resistance to rotation stabilizes the planar configuration of this functional group. As a result, certain disubstituted alkenes may exist as a pair of configurational stereoisomers, often designated cis and trans. The essential requirement for this stereoisomerism is that each carbon of the double bond must have two different substituent groups (one may be hydrogen). This is illustrated by the following general formulas. In the first example, the left-hand double bond carbon has two identical substituents (A) so stereoisomerism about the double bond is not possible (reversing substituents on the right-hand carbon gives the same configuration). In the next two examples, each double bond carbon atom has two different substituent groups and stereoisomerism exists, regardless of whether the two substituents on one carbon are the same as those on the other.
Some examples of this configurational stereoisomerism (sometimes called geometric isomerism) are shown below. Note that cycloalkenes smaller than eight carbons cannot exist in a stable trans-configuration due to ring strain. A similar restriction holds against cycloalkynes smaller than ten carbons. Since alkynes are linear, there is no stereoisomerism associated with the carbon-carbon triple bond.
Nomenclature of Alkene Stereoisomers Configurational stereoisomers of the kind shown above need an additional nomenclature prefix added to the IUPAC name, in order to specify the spatial orientations of the groups attached to the double bond. Thus far, the prefixes cis-and trans- have served to distinguish stereoisomers; however, it is not always clear which isomer should be called cis and which trans. For example, consider the two compounds on the right. Both compound A (1-bromo-1-chloropropene) and compound B ( 1-cyclobutyl-2-ethyl-3-methyl-1-butene) can exist as a pair of configurational stereoisomers (one is shown). How are we to name these stereoisomers so that the configuration of each is unambiguously specified? Assignment of a cis or trans prefix to any of these isomers can only be done in an arbitrary manner, so a more rigorous method is needed. A competely unambiguous system, based on a set of group priority rules, assigns a Z (German, zusammen for together) or E (German, entgegen for opposite) to designate the stereoisomers. In the isomers illustrated above, for which cis-trans notation was adequate, Z is equivalent to cis and E is equivalent to trans. To see how complex stereoisomeric alkenes can be named by the IUPAC system Click Here.
These problems test the ability to recognize, draw and name alkene and cycloalkane stereoisomers
Remember, when the group of atoms that make up the molecules of different isomers are bonded together in fundamentally different ways, we refer to such compounds as constitutional isomers. For example, in the case of C5H10 hydrocarbons, most of the isomers are constitutional. Shorthand structures for five of these isomers are shown below with their IUPAC names.
Note that the fifteen atoms that make up these isomers are connected or bonded in very different ways. As is true for all constitutional isomers, each different compound has a different IUPAC name. Furthermore, the molecular formula provides information about some of the structural features that must be present in the isomers (e.g. a ring or a double bond). Among the formulas of the four monocyclic isomers shown here, the last does not unambiguously designate a single unique compound. Two isomers having the constitution of 1,2-dimethylcyclopropane exist; their properties, together with those of the 1,1-dimethyl isomer are listed in the following table.
To understand the origin of this isomerism it is necessary to think three-dimensionally, and to consider the orientation or configuration of the atoms and groups in space. The three carbons of the cyclopropane ring define a plane, and the substituent atoms or groups bonded to these carbon atoms are directed in space above and below this plane. In the case of the 1,2-dimethyl isomers, the two methyl groups may lie on the same side of the ring, called a cis configuration, or on opposite sides, a trans configuration, as shown in the following diagram. From evidence that will not be described here, isomer A has the cis configuration, and isomer B the trans configuration. This configurational isomerism is commonly called stereoisomerization.
Drawing and Naming Cycloalkane Stereoisomers Stereoisomers are often found in disubstituted (and higher substituted) cyclic compounds. Chemists use heavy, wedge-shaped bonds to indicate a substituent located above the average plane of the ring (note that cycloalkanes larger than three carbons are not planar), and a hatched line for bonds to atoms or groups located below the average ring plane. As noted above, disubstituted cycloalkane stereoisomers may be designated by the nomenclature prefix cis, if the substituents are bonded on the same side of the ring, or trans for substituents oriented on opposite sides of the ring. The stereoisomeric 1,2-dibromocyclopentanes shown to the right are an example. In general, if any two sp3 carbons in a ring have two different substituent groups (not counting other ring atoms) stereoisomerism is possible. Four other examples of this kind of sterioisomerism in cyclic compounds are shown below.
If more than two ring carbons have different substituents (not counting other ring atoms) the stereochemical notation distinguishing the various isomers becomes more complex. For examples of how such compounds are named in the IUPAC system Click Here.
Structural formulas show the manner in which the atoms of a molecule are bonded together (its constitution), but do not generally describe the three-dimensional shape or configuration of a molecule. As noted above, when distinct bonding configurations permit the existence of stereoisomers, special bond notations (e.g. wedge and hatched lines) are used to distinguish the structures, and a cis or trans prefix is used to provide unique names. In this section we shall extend our three-dimensional view of molecular structure to include compounds that normally assume an array of equilibrating three-dimensional spatial orientations, which together characterize the same isolable compound. We call these different spatial orientations of the atoms of a molecule that result from rotations or twisting about single bonds conformations. In the case of hexane, we have an unbranched chain of six carbons which is often written as a linear formula: CH3CH2CH2CH2CH2CH3. We know this is not strictly true, since the carbon atoms all have a tetrahedral configuration. The actual shape of the extended chain is therefore zig-zag in nature. However, there is facile rotation about the carbon-carbon bonds, and the six-carbon chain easily coils up to assume a rather different shape. Many conformations of hexane are possible and two are illustrated below.
For an animation of conformational motion in hexane Click Here
1. Ethane Conformers The simple alkane ethane provides a good introduction to conformational analysis. Here there is only one carbon-carbon bond, and the rotational structures (rotamers) that it may assume fall between two extremes, staggered and eclipsed. In the following description of these conformers, several structural notations are used. The first views the ethane molecule from the side, with the carbon-carbon bond being horizontal to the viewer. The hydrogens are then located in the surrounding space by wedge (in front of the plane) and hatched (behind the plane) bonds. If this structure is rotated so that carbon #1 is canted down and brought closer to the viewer, the "sawhorse" projection is presented. Finally, if the viewer looks down the carbon-carbon bond with carbon #1 in front of #2, the Newman projection is seen.
Bond Repulsions in Ethane
As a result of bond-electron repulsions, illustrated on the right above, the eclipsed conformation is less stable than the staggered conformation by roughly 3 kcal/mole. This destabilization is called eclipsing strain. The most severe repulsions in the eclipsed conformation are depicted by the red arrows. There are six other less strong repulsions that are not shown. In the staggered conformation there are six equal bond repusions, four of which are shown by the blue arrows, and these are all substantially less severe than the three strongest eclipsed repulsions. Consequently, the potential energy associated with the various conformations of ethane varies with the dihedral angle of the bonds, as shown below. Although the conformers of ethane are normally in rapid equilibrium with each other, the 3 kcal/mole energy difference leads to a substantial preponderance of staggered conformers (> 99.9%) at any given time.
2. Butane Conformers The hydrocarbon butane has a larger and more complex set of conformations associated with its constitution than does ethane. Of particular interest and importance are the conformations produced by rotation about the central carbon-carbon bond. Among these we shall focus on two staggered conformers (A & C) and two eclipsed conformers (B & D), shown below in several stereo-representations. As in the case of ethane, the staggered conformers are more stable than the eclipsed conformers by 2.8 to 4.5 kcal/mole. Since the staggered conformers represent the chief components of a butane sample they have been given the identifying prefix designations anti for A and gauche for C.
The following diagram illustrates the change in potential energy that occurs with rotation about the C2–C3 bond. The model on the right is shown in conformation D, and by clicking on any of the colored data points on the potential energy curve, it will change to the conformer corresponding to that point. The full rotation will be displayed by turning the animation on. This model may be manipulated by click-dragging the mouse for viewing from any perspective.
For a more extensive discussion of rotamer analysis Click Here.
Although the customary line drawings of simple cycloalkanes are geometrical polygons, the actual shape of these compounds in most cases is very different.
Cyclopropane is necessarily planar (flat), with the carbon atoms at the corners of an equilateral triangle. The 60º bond angles are much smaller than the optimum 109.5º angles of a normal tetrahedral carbon atom, and the resulting angle strain dramatically influences the chemical behavior of this cycloalkane. Cyclopropane also suffers substantial eclipsing strain, since all the carbon-carbon bonds are fully eclipsed. Cyclobutane reduces some bond-eclipsing strain by folding (the out-of-plane dihedral angle is about 25º), but the total eclipsing and angle strain remains high. Cyclopentane has very little angle strain (the angles of a pentagon are 108º), but its eclipsing strain would be large (about 10 kcal/mol) if it remained planar. Consequently, the five-membered ring adopts non-planar puckered conformations whenever possible. Rings larger than cyclopentane would have angle strain if they were planar. However, this strain, together with the eclipsing strain inherent in a planar structure, can be relieved by puckering the ring. Cyclohexane is a good example of a carbocyclic system that virtually eliminates eclipsing and angle strain by adopting non-planar conformations, such as those shown below. Cycloheptane and cyclooctane have greater strain than cyclohexane, in large part due to transannular crowding (steric hindrance by groups on opposite sides of the ring).
1. Some Conformations of Cyclohexane Rings
These conformations may be examined as interactive models by Clicking Here.
Investigations concerning the conformations of cyclohexane were initiated by H. Sachse (1890) and E. Mohr (1918), but it was not until 1950 that a full treatment of the manifold consequences of interconverting chair conformers and the different orientations of pendent bonds was elucidated by D. H. R. Barton (Nobel Prize 1969 together with O. Hassel). The following discussion presents some of the essential features of this conformational analysis. On careful examination of a chair conformation of cyclohexane, we find that the twelve hydrogens are not structurally equivalent. Six of them are located about the periphery of the carbon ring, and are termed equatorial. The other six are oriented above and below the approximate plane of the ring (three in each location), and are termed axial because they are aligned parallel to the symmetry axis of the ring. In the stick model shown on the left below, the equatorial hydrogens are colored blue, and the axial hydrogens are red. Since there are two equivalent chair conformations of cyclohexane in rapid equilibrium, all twelve hydrogens have 50% equatorial and 50% axial character.
Because axial bonds are parallel to each other, substituents larger than hydrogen generally suffer greater steric crowding when they are oriented axial rather than equatorial. Consequently, substituted cyclohexanes will preferentially adopt conformations in which large substituents assume equatorial orientation. In the two methylcyclohexane conformers shown above, the methyl carbon is colored blue. When the methyl group occupies an axial position it suffers steric crowding by the two axial hydrogens located on the same side of the ring. This crowding or steric hindrance is associated with the red-colored hydrogens in the structure. A careful examination of the axial conformer shows that this steric hindrance is due to two gauche-like orientations of the methyl group with ring carbons #3 and #5. The use of models is particularly helpful in recognizing and evaluating these relationships.
These conformations may be examined as interactive models by Clicking Here
To view an animation of the interconversion of cyclohexane chair conformers Clicking Here
The relative steric hindrance experienced by different substituent groups oriented in an axial versus equatorial location on cyclohexane may be determined by the conformational equilibrium of the compound. The corresponding equilibrium constant is related to the energy difference between the conformers, and collecting such data allows us to evaluate the relative tendency of substituents to exist in an equatorial or axial location. The left hand structures and table in the following diagram summarize the free energy differences between equatorial and axial orientations of some simple groups. These energies are commonly reported as A values. An axial methyl group is hindered by two gauche butane interactions, each accounting for ca. 0.9 kcal/mol. Since an axial ethyl group may rotate so that it appears no larger than a methyl to the remaining axial hydrogens on the same side of the ring, its A value is the same as methyl. Larger alkyl groups have increased A values, comensurate with increased crowding with the axial hydrogens.
The apparent "size" of a substituent is influenced by its width and bond length to cyclohexane, as evidenced by the fact that an axial vinyl group is less hindered than ethyl, and iodine slightly less than chlorine. The trimethylsilyl group has an A value roughly half that of a tert-butyl group, reflecting the longer bond length of C–Si. The heterocyclic compounds on the right side of the diagram illustrate the decreased axial hinderance that results from the absence of nearby axial hydrogens. From the smaller but significant energy differences shown, it may be concluded that the steric hindrance of non-bonding electron pairs on oxygen cannot be ignored. Other factors in these cases are the shorter bond length and tighter C-O-C angle, which may act to increase hindrance, as shown by the lower right example. A complete table of the free energies referred to as A values may be examined by Clicking Here.
2. Substituted Cyclohexane Compounds Because it is so common among natural and synthetic compounds, and because its conformational features are rather well understood, we shall focus on the six-membered cyclohexane ring in this discussion. In a sample of cyclohexane, the two identical chair conformers are present in equal concentration, and the hydrogens are all equivalent (50% equatorial & 50% axial) due to rapid interconversion of the conformers. When the cyclohexane ring bears a substituent, the two chair conformers are not the same. In one conformer the substituent is axial, in the other it is equatorial. Due to steric hindrance in the axial location, substituent groups prefer to be equatorial, so that chair conformer predominates in the equilibrium. We noted earlier that cycloalkanes having two or more substituents on different ring carbon atoms exist as a pair (sometimes more) of configurational stereoisomers. Now we must examine the way in which favorable ring conformations influence the properties of the configurational isomers. Remember, configurational stereoisomers are stable and do not easily interconvert; whereas, conformational isomers normally interconvert rapidly. In examining possible structures for substituted cyclohexanes, it is useful to follow two principles.
(i) Chair conformations are generally more stable than other possibilities. (ii) Substituents on chair conformers prefer to occupy equatorial positions due to the increased steric hindrance of axial locations.
The following equations and formulas illustrate how the presence of two or more substituents on a cyclohexane ring perturbs the interconversion of the two chair conformers in ways that can be predicted.
In the case of 1,1-disubstituted cyclohexanes, one of the substituents must necessarily be axial and the other equatorial, regardless of which chair conformer is considered. Since the substituents are the same in 1,1-dimethylcyclohexane, the two conformers are identical and present in equal concentration. In 1-t-butyl-1-methylcyclohexane the t-butyl group is much larger than the methyl, and that chair conformer in which the larger group is equatorial will be favored in the equilibrium( > 99%). Consequently, the methyl group in this compound is almost exclusively axial in its orientation. In the cases of 1,2-, 1,3- and 1,4-disubstituted compounds the analysis is a bit more complex. It is always possible to have both groups equatorial, but whether this requires a cis-relationship or a trans-relationship depends on the relative location of the substituents. As we count around the ring from carbon #1 to #6, the uppermost bond on each carbon changes its orientation from equatorial (or axial) to axial (or equatorial) and back. It is important to remember that the bonds on a given side of a chair ring-conformation always alternate in this fashion. Therefore, it should be clear that for cis-1,2-disubstitution, one of the substituents must be equatorial and the other axial; in the trans-isomer both may be equatorial. Because of the alternating nature of equatorial and axial bonds, the opposite relationship is true for 1,3-disubstitution (cis is all equatorial, trans is equatorial/axial). Finally, 1,4-disubstitution reverts to the 1,2-pattern.
The conformations of some substituted cyclohexanes may be examined as interactive models by Clicking Here.
These five problems concern the recognition of different conformations of a given constitutional structure. Axial and equatorial relationships of cyclohexane substituents are also examined.