Summary

The different spatial arrangments that a molecule can adopt due to rotation about σ bonds are called conformations and hence conformational isomers orconformers. The study of the energy changes that occur during these rotations is called conformational analysis. This is important because the structure of a molecule can have a significant influence on the molecular properties, including dictating the outcome of a reaction. Although the ideas are developed for the simplest functional groups, the alkanes, the same principles can be expanded and applied to other functional groups.

Conformational Language

Key terms glossary Drawing and interpretting Important diagrams (wedge-dash, sawhorse, Newman,

Cyclohexane)

Basics

Energetics What are conformational isomers ?

Conformational Analysis

Simple alkanes : Methane, Ethane and Propane Higher alkanes : Butane and beyond Cycloalkanes : C3 to C5 C6H12, Cyclohexane Substituted cyclohexanes Polycyclics Heterocycles Interesting Molecules Sample questions Crossword

Drill Problems

More practice problems ?

Conformational Language

An alphabetical list of key terms in the language of conformational analysis is provided below, linked to the more detailed descriptions within the chapter pages  

Anti

Description given to two substitutents attached to adjacent atoms when their bonds are at 180o with respect to each other.

Eclipsed

A high energy conformation where the bonds on adjacent atoms are aligned with each other.

Staggered

A low energy conformation where the bonds on adjacent atoms bisect each other, maximising the separation.

Gauche

Description given to two substitutents attached to adjacent atoms when their bonds are at 60o with respect to each other.

Syn

Description given to two substitutents attached to adjacent atoms when their bonds are at 0o with respect to each other.

ConformationsDifferent spatial arrangments that a molecule can adopt due to rotation about sigma bonds.

ConformersContracted version of conformational isomers.

RotamersAlternative expression for conformational isomers.

Conformational isomers

Structures that can be interconverted by rotation about σ bonds.

CycloalkaneAn ring containing only C-C bonds.

HeteroatomA non-carbon atom such as O,N,S etc. 

HeterocycleA cyclic molecule that includes a heteratom such as O,N,S etc. as part of the ring.

Puckered

In general terms, puckered means "wrinkled, folded or creased". In conformational analysis this is used to refer to the non-planar geometry of a cyclic structure.

Ring flippingThe process by which a ring changes it's conformation.

Axial

A position on a cycloalkane in which the bond to the ring is perpendicular to the average plane of the ring (i.e. pointing towards the poles). Most commonly encountered in the chair conformation of cyclohexane.

Equatorial

A position on a cycloalkane in which the bond to the ring is approximately in the average plane of the ring (i.e. around the equator). Most commonly encountered in the chair conformation of cyclohexane.

ChairThe most stable conformation for cyclohexane.

BoatA high energy conformation of cyclohexane that occurs during ring flipping.

StrainEnergy associated with a system due to its geometry.

Angle strain

Destabilisation due to distortion of a bond angle from its optimum value caused by the electrostatic repulsion of the electrons in the bonds.

Van der Waals   strain

Destabilisation due to the repulsion between the electron clouds of atoms or groups. Also known as Van der Waals repulsion. This occurs when atoms or groups are too close to each other due to the electrostatic repulsion of the electrons.

Steric strainA composite of the other strains (angle, torsional, Van der Waals) within a molecule.

Torsional strain

Destabilisation due to the repulsion between pairs of bonds caused by the electrostatic repulsion of the electrons in the bonds.

Torsional angle

Angle between C-X and C-Y bonds in a X-C-C-Y system when viewed along the C-C bond. Rotation about the C-C bond will change this torsional angle.  This is also known as a dihedral angle.

Ring strain

The destabilisation of a cyclic structure compared to a related non-cyclic structure, mainly due to angle and torsional strain. This extra energy is released when the ring is broken.

Drawing and Understanding Diagrams

    The ability to draw and interpret the different diagrams that are used to represent the different conformations is an important skill to acquire. Maximise your artistic talents !

The only person that will be decieved by your poor diagrams is you ! Your instructor will be able to tell instantly that you are struggling....

    These diagrams allow 3D representations of molecules to be drawn on the 2D world of a piece of paper (or computer screen), in a similar way to which one can look at the plans for a house.

wedge-dash sawhorse Newman    cyclohexane

Wedge-dash diagrams Usually drawn with two bonds in the plane of the page, one infront, and one behind to give the molecule perspective. When drawing wedge-dash it is a good idea to visualise the tetrahedral arrangement of the groups and try to make the diagram "fit" this. As a suggestion, they seem to be most effective when the "similar" pairs of bonds (2-in-plane, 2-out-of-plane) are next to each other, see below:

Sawhorse Sawhorse diagrams are similar to wedge-dash diagrams, but without trying to use "shading" to denote the perspective. The representation to the right of propane has been drawn so that we are looking at the molecule which is below us and to our left.

Newman Projections

These projections are drawn by looking directly along a particular bond in the system (here a C-C bond) and arranging the substituents symmetrically around the atoms at each end of that bond. The protocol requires that the atoms within the central bond are defined as shown below:

In order to draw a Newman projection from a wedge-dash diagram, it is useful to imagine putting your "eye" in line with the central bond in order to look along it.

Let's work through an example, consider drawing a Newman projection by looking at the following wedge-dash diagram of propane from the left hand side.

First draw the dot and circle to represent the front and back C respectively Since the front carbon atom has an H atom in the plane of the page pointing up we can

add that first The back carbon atom has an H atom in the plane of the page pointing down Now add the other bonds to each C so that it is symmetrical The groups / bonds (blue) that were forward of the plane of the page in the original

wedge-dash diagram are now to our right Those behind (green) the plane are now to our left

Now you try the same thing, but looking from the right to generate the other Newman projection.

Drawing Cyclohexanes Drawing cyclohexane so that it looks like a chair can be the key to appreciating the axial and equatorial positions. If you are unable to draw good looking structures that clearly show axial and equatorial positions, then your instructor is probably going to assume that you don't know.

By not mastering the trick of drawing cyclohexanes the only person that really suffers is you the student. You deprive yourself of the knowledge and the chance to appreciate it and what it means. Believe me, it will be needed later.

The first step is drawing the chair itself.  Although the chair "looks better" when slightly angled, it maybe easier to "learn" to draw it with the middle portion horizontal.

Energetics

Fundamentals of electrostatics Types of strain

The predominant forces involved in chemistry are electrical in origin based on the physics associated with Coulomb's Law of electrostatics. The basics are reviewed below:   The force between two charged particles q1 and q2 is inversely proportional to the distance, r, between them.

If the particles are of opposite polarity, then the force is attractive.

As an example, the attraction of electrons to an atomic nucleus.  

If the particles are of the same polarity, then the force is replusive.

As an example, electron pair repulsion used in VSEPR

IMPORTANT IMPLICATIONS :  Electron pairs repel each other. As a result, molecules are most stable when pairs of electrons are as far apart from each other as possible. When the pairs of electrons are too close together, then the molecule is destabilised and it is at higher energy. Remember, the most stable states are those of lowest energy.

(You should already know this from General Chemistry and Chapter 1, VSEPR.)

Conformational analysis is essentially an investigation of forces and energies associated with the interactions of pairs of electrons (these could be pairs of electrons in bonds or lone pairs). Strain is the term used to for the energy associated with a system due to its geometry. There are various types of strain that we need to be familar with. These and associated terms are described below:  

Steric strain

The overall strain in a molecule due to the non-bonded interactions of atoms or groups of atoms that are in close proximity so that their electrons repel each other.  It can be broken down into other types of strain as desecribed below.

Angle strain

If the angle between a pair of bonds in an X-C-Y system is less than the optimal value(e.g. 109.5o at a tetrahedral center), then there is a destabilisation due to the electrostatic repulsion of the electrons in the bonds. Note that the two bonds share a common atom, here C.

Van der Waals strain  

 

If the electron clouds of a pairs of atoms or group of atoms (such as a methyl group) are too close to each other, then there is a destabilisation due to the electrostatic repulsion of the electron clouds. Note that these groups don't even have to be parts of the same molecule. This is also known as Van der Waals repulsion.

Torsional strain    

 

The electrons in a C-X bond are replled by those in a C-Y bond within a  X-C-C-Y system. When this pair of bonds are too close to each other, then there is a destabilisation due to the electrostatic repulsion of the electrons in the bonds. (note students often have difficulty with this type of strain since they confuse it with angle strain)

Torsional angle

For example, the angle between C-X and C-Y bonds in a X-C-C-Y system. Also known as a dihedral angle. Rotation of the single bond C-C results in a change in the torsional angle. 

Ring strain  

If we compare the energy of a cyclic structure compared to a related non-cyclic structure (e.g.

 

cyclopropane and propane), then typically the cyclic structure is less stable, mainly due to angle and torsional strain. This extra energy is released when the ring is broken and is called ring strain.

What are Conformational Isomers ?

In Chapter 1 we looked at constitutional isomers and we started to grow "an isomer tree".  We now need to grow the next branch in order to start our investigation of conformational isomers.   If you

"click" on the named boxes there is a link to a definition and an example.

 

Isomers are compounds with the same molecular formulae but that are structurally different in some way. It is important to be able to recognise isomers because they can have different chemical, physical properties and biological properties.

 

 

Constitutional isomers differ in the order in which the atoms are connected so they can contain different functional groups and / or bonding patterns (e.g. branching)

example: 1-propanol, 2-propanol and ethyl methyl ether (C3H8O)

 

Stereoisomers have the same functional groups and connectivities, they differ only in the arrangement of atoms and bonds in space.

 

 

Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation (twisting) about σ bonds, and are often rapidly interconverting at room temperature.

example 1: butane : anti (left) and syn (center). Rotation about the C2-C3 σ bond is animated (right). Try rotating the model to look along the C-C to see the two extreme forms.

example 2: cyclohexane : chair (left) and boat (right).These two forms can be interconverted by twisting the ring structure.

Alkanes

Let's start with simple alkanes so we can prepare ourselves for the more complex world that lies beyond.....

Methane Ethane Propane

Methane: CH4  

Although σ bonds are able to rotate about the internuclear axis, the spherical symmetry of H atoms means that methane has a single unique

conformation. 

 

Ethane: CH3-CH3

Rotation about the C-C bond in ethane (see the JSMOL animation to the right) produces different conformations. Although an infinite number of conformations are possible, the staggered and eclipsed conformations which represent the most and least stable respectively are the two most important.  Try rotating the 3D model of the animation so that you are looking directly along the C-C bond to see the interconversion of the two extreme conformations.The differences between these two conformations are most apparent when viewed directly down the C-C bond, as in a Newman projection, see below: 

STAGGERED Look at how the each H-C-H bond angle is bisected by a C-H bond on the adjacent C atom. This is the most stable conformation for ethane since the torsional strain is minimised. The staggered conformation is 12kJ/mol (2.9 kcal/mol) more stable than the eclipsed conformation  (below).

ECLIPSED Think like an astronomer....each of  the C-H bonds is aligned with a C-H bond on the adjacent C atom so that the H attached to the front C obscures (eclipses)  those on the rear C

The animation below shows how the potential energy of the ethane molecule varies for a full rotation about the central C-C bond. Use the controls to show the energies of the important conformations.

Propane: CH3-CH2-CH3  

Although there are 2 C-C bonds in propane, they are equivalent and rotation produces conformations that are similar to those of ethane except that the "extra" methyl group is interacting with the H atoms. 

These can be seen by in the 3D

model of propane to the right.   

 

Higher Alkanes

The same basic ideas of conformational analysis developed previously for simple alkanes also apply, but some new situations are encountered.

Butane: CH3-CH2-CH2-CH3

In butane it is the rotation about the C2-C3 bond that is of most interest since the relative position of the two methyl groups is important. 

This can be seen most easily by rotating the molecule to view it down the C2-C3 bond. Try rotating the 3D model in the animation so that you are looking directly along the C-C bond to see the interconversion of the two conformations.

The more important conformations are shown below:

ANTI a staggered conformation with the Me groups at 180o with respect to each other. This is the most stable conformation since the Me groups are as far apart as possible.

GAUCHE a staggered conformation with the Me groups at 60o with respect to each other.

SYN an eclipsed conformation with the Me groups at 0o with respect to each other. This is the least stable conformation due to the steric strain caused by the proximity of the Me groups and the torsional strain of the eclipsed bonds.

GAUCHE a staggered conformation with the Me groups at 60o with respect to each other

note: the two gauche conformations are not quite the same, try to convince yourself of this.  How are they related to each other ?

They are non-superimposable mirror iamges (so they are enantiomers)

Question: Hydrocarbons are often drawn as simple "zig-zag" structures an example of which is given below.

What type of conformation does this represent ?

ANSWER 

The zig-zag is an anti conformation - the most stable conformation

Cycloalkanes

Cycloalkanes literally means "cyclic alkanes", which means ring structures containing only C-C and C-H bonds.

The C atoms in cycloalkanes are predicted to be sp3 hybridised which requires optimal C-C-C bond angles of 109.5o

These structural units are commonly encountered in natural compounds such as steroids, with cyclopentanes and cyclohexanes being the most common.

Other than the smallest ring system cyclopropane (which must be planar), cycloalkanes are "puckered"

Puckering typically reduces ring strain (i.e. makes it more stable) by lowering torsional strains but this is offset by slightly increased angle strain.

Ring strain : cyclopropane > cyclobutane > cyclopentane > cyclohexane

The most stable conformations of the first three cycloalkanes (the smallest three) are shown below where they can be contrasted with the planar conformation. In order to be able to compare the strain in each member of the cycloalkane series, the heat of combustion per methylene (i.e. -CH2-) is also given (see note below the table). The smaller this number is the less ring strain there is. In each case, you should manipulate the 3D-JSMOL images to visualise the deviation from planarity and the effect this has on the eclipsing interactions of adjacent C-H bonds and C-C bonds (hint turn the model to "see" the Newman projections).

C3H6

CYCLOPROPANE ΔHc / CH2 = -697 kJ/mol

(-166.6 kcal/mol)

ANALYSIS 

The 3 C atoms in cyclopropane must be planar (due to the rules of geometry

where 3 points define a plane). This means the C-C bonds are fully eclipsed (torsional strain). This means the C-H bonds are fully eclipsed (6 pairs, torsional strain). By definition, the C-C-C bond angles are 60o (angle strain). Overall, this means high ring strain.

C4H8

CYCLOBUTANE ΔHc / CH2 = -681 kJ/mol (-162.7 kcal/mol)

ANALYSIS 

The 4 membered ring has a little bit of flexibility and can twist to be non-planar (puckered).

The angle of the fold is of the order of 28o

This means the C-C bonds are only partially eclipsed (reduces torsional strain). This means the C-H bonds are only partially eclipsed (reduces torsional strain). The C-C-C bond angles close to 90o (angle strain). Overall, this means high ring strain.

C5H10

CYCLOPENTANE ΔHc / CH2 = -658 kJ/mol

(-157.3 kcal/mol)

ANALYSIS 

The 5 membered ring has some flexibility and can twist to be non-planar (puckered).

The most stable conformation is referred to as the "envelope" This means the C-C bonds are only partially eclipsed (reduces torsional strain). This means the C-H bonds are only partially eclipsed (reduces torsional strain). The C-C-C bond angles close to 105o (a little angle strain).

Overall, this means relatively low ring strain.

Cyclohexane

This is a common and therefore important ring system, what should you know ?

How to draw cyclohexanes so you can convey your knowledge ! The most stable conformation is the chair There are other less stable conformations such as the boat and the twist boat. Ring flipping interconverts chair conformations. There are two types of substituent positions around a chair cyclohexane axial

and equatorial.

C6H12

CYCLOHEXANE ΔHc / CH2 = -653 kJ/mol (-156.1 kcal/mol)

The most stable conformation of cyclohexane is the chair form shown to the right. The C-C-C bonds are very close to 109.5o, so it is almost free of angle strain. It is also a fully staggered conformation and so is free of torsional strain.  Rotate the molecule in the JSMOL image to show this just like a Newman projection so that you can inspect the staggered C-H and C-C bonds. 

The chair conformation is the most stable conformation of cyclohexane.

In chair cyclohexane there are two types of positions, axial and equatorial. The axial positions point perpendicular to the plane of the ring, whereas the equatorial positions are around the plane of the ring. You should notice that adjacent axial postions point in opposite directions. The same is true for the equatorial positions. The axial and equatorial positions can be highlighted in the JSMOL image to the right

A second, much less stable conformer is the boat conformation. This too is almost free of angle strain, but in contrast has torsional strain associated with eclipsed bonds at the four of the C atoms that form the side of the boat. Rotate the molecule in the JSMOL image to show this just like a Newman projection. In addition, a steric interaction of the H atoms inside the "bow" and the "stern", known as the flagpole interaction also destabilises the boat.

A third conformation is produced by twisting the boat to give the twist or skew-boat conformation. The twist relieves some of the torsional strain of the boat and moves the flagpole H further apart reducing the steric strain. Consequently the twist boat is slightly more stable than the boat. 

Conformational rotation of cyclohexane interconverts the conformations. This proceeds from one chair to twist boat to boat to twist boat to the other chair

conformation. This process is often referred to as "ring flipping".

Watch the JSMOL animation carefully and look for the two chair forms, stop and rotate the animation if needed. The animation will pause at the chair conformation before

continuing.

An important feature of this process is that the axial and equatorial positions are interchanged. If you use the colour coding you should be able to see that a position that

was axial in one chair is equatorial in the other and vice versa.

An important feature of this process is that the axial and equatorial positions switch.  If you watch carefully you will see that a position that was axial in one chair is equatorial in the other and vice versa.

Substituted Cyclohexanes

Cyclohexane substituents can be found in either axial or equatorial positions. However, in general, equatorial substituents tend to be preferred because they are more stable because of reduced steric interactions.

Let's consider an example, methycyclohexane. In the equatorial system, the methyl group has space around it as it is pointed away from the rest of the ring. The C-C bond that connects the methyl group is anti to the two C-C bonds in the rest of the ring system which means there is minimal torsional strain.

However, in the axial conformation, the methyl group is closer to the rest of the ring. There is an unfavourable steric interaction between the methyl group with the two axial hydrogen atoms on the same face of the ring. This destabilises the axial conformation. In the JSMOL images below, this 1,3-diaxial interaction can be highlighted and contrasted with the equatorial conformer. The close proximity of the substituent and the H atoms is most obvious when looking at the space filling model. In addition, the C-C bond that connects the methyl group is gauche to the two C-C bonds in the rest of the ring system which means there is also some torsional strain.

Make sure you can see the steric differences between the axial and equatorial situations.

The larger the alkyl substituent is, the greater the preference for the equatorial position since the larger the group the greater the steric interaction with the axial hydrogens.

Polycyclic Systems

Both nature and human kind has created many examples of compounds that contain more than one ring system. These can be classified depending on how many rings are present and how the rings are joined together.

If there is a single atom common to two rings, then the system is said to be "spirocyclic" and the central atom can be described as the "spirocenter". The simplest example is spiropentane. 

 If two or more atoms are shared between more than one ring then the system is said to be "polycyclic" in general terms or as bicyclic, tricyclic, tetracyclic etc. depending on how many rings systems are present.  The simplest polycyclic system is bicyclobutane.  When there are two common atoms in the rings, then it is a "fused" system, as in bicyclobutane. 

 If there are more than two common atoms then the a "bridged" system is obtained, the simplest example being bicyclo[1.1.1]pentane. 

 

Heterocycles

Of course atoms other than carbon can occur as part of the cyclic structure. Such atoms, which are known as heteroatoms, e.g. N, O, S give rise to heterocycles.  From a conformational analysis presepective, these heterocycles are, in general, very similar to the analogous hydrocarbons, check out the JSMOL images of a few common simple heterocylces shown below.

Tetrahydrofuran (THF)

Pyrrolidine

Piperidine

Morpholine

This page contains some examples of interesting polycyclic and / or heterocyclic molecules used as pharmaceuticals. Look at the JSMOL images to see the types and shapes of the ring systems that are present.

RANITIDINE : C13H22N4O3S,  mol. wt. = 314.41 g/mol  Physical properties: Solid, mp = 69-70oC. US patent is held by Allen and Hanburys.  The hydrochloride of Ranitidine is called Zantac, one of the most prescribed drugs in the western world. Zantac is an off white solid, mp = 133-134 oC. It is soluble in acetic acid, water and methanol, sparingly soluble in ethanol, insoluble in chloroform.  Ranitidine is a histamine H2-receptor antagonist which inhibits gastric acid secretion.  Therapeutically it is used as an antiulcerative.PRONTOSIL : C12H13N5O2S,  mol. wt. = 291.33 g/mol  The hydrochloride salt is an orange-red cyrstaline material, mp : 248-250 oC, solubility: 1g in 400 ml water, much more soluble in hot water, soluble in alcohol, acetone, fats and oils. Prontosil was original prepared as an "azo-dye" and used for dyeing wool fibres. However, it was part of an in vivo study for antibacterial activity (found to be active against Gram-positive infections) and became a prototype compound that led to the development of the important sulphonamide antibacterials. Prontosil was first drug introduced to treat bacterial infections. Therapeutically it is used as an antibacterial, but it is also used as a specific stain for carbonic anhydrase in polyacrylamide gels. PROMAZINE : C17H20N2S, mol. wt. = 284.43 g/mol  Physical properties: an oily liquid, having an "amine" odour. bp(0.3) : 203-210 oC.  Prepared by heating a xylene solution of phenothiazine and 3-dimethylamino-1-chloro-propane in the presence of sodamide. US patent for Promazine is held by Rhone-Poulenc.  The hydrochloride salt, Prazine (also known as Talofen or Sparine) is a white/yellow crystalline material that oxidises in air. One gram is soluble in 3 ml of water. it is also soluble in alcohols and chloroform, insoluble in diethyl ether and benzene. Aqueous solutions are slightly acidic to litmus.  Therapeutically it is used as an antipsychotic and an antihistamine in man and as a tranquilizer for animals. NOVOCAIN : C13H20N2O2.HCl,  mol.  wt. = 273.07 g/mol  Novocain is the hydrochloride salt of another pharmaceutical, Procaine. Novocain is a crystaline material:mp = 153-156 oC. Numbing taste. Air stable. Solubility: 1g dissolvesin 1ml water and 30ml of alcohol, slightly soluble in chloroform, virtuallyinsoluble in diethyl ether. pH of 0.1M solution is 6.0. Aqueous solutionscan be sterilised by boiling. LD50 (mice mg/kg) = 660.  Novocain was synthesised to replace cocaine due to the abuse of cocaine.It was designed to have the same pain-killing properties but not the psychologicalside effects. Therapeutically used as a local anesthetic for humans and animals. LIDOCAINE : C14H22N2O, mol. wt. = 234.34 g/mol  Physical properties: crystaline needles (from benzene or alcohol) mp = 68-69oC, bpt (4mm) = 180-182oC.  Soluble in chloroform, benzene, ether and alcohol. Insoluble in water. 

Lidocaine was developed from Procaine (ie Novocain), the structure of which is shown above. Compare the two structures. Due to the presence of a labile ester bond, Procaine has only a short lifetime/duration of action. Changing this to a more stable amide linkage as in Lidocaine provides a material with a longer lifetime and therefore duration. The US patent is held by Astra.  Also known as Lignocaine and Xylocaine amongst many other names.  Therapeutically it is used as a local anesthetic and a class IB antiarrhythmic.DIAZEPAM : C16H13ClN2O, mol. wt. = 284.74 g/mol  Physical properties: crystaline plates (from acetone and petroleum ether) mp = 125-126oC.  pKa = 3.4. Soluble in chloroform, dimethyl formamide, benzene, acetone and alcohol. Slightly soluble in water. LD50 (orally for rats) = 710mg/kg  This is a controlled substance in US code of Federal Regulations. US patent is held by Hoffmann-La Roche.  Also known as Valium, Novazam amongst many other names.  Therapeutically it is a anxiolytic, a skeletal muscle relaxant.NORETHINDRONE : C20H26O2, mol. wt. = 298.43 g/mol  Physical properties: crystaline (from ethyl acetate) mp = 203-204oC. Specific rotation = -31.7 in chloroform.  Prepared from 19-nor-4-androstene-3,17-dione. US patent is held by Syntex.  Also known as Coniudag, Menzol, Micronor, Micronovum, Mini-Pe, Norcuolut, Noriday, Norluten, Norlutin, Nor-Qd, Primolut N, and, Utovlan.  Norethindrone is a synthetic steroid and was developed since it was known that natural steroids have potent physiological effects.  Therapeutically it is a progestogen. Norethindorne and its acetate with estrogen is used as an oral contraceptive. The enanthate is an injectable contraceptive.MIFEPRISTONE : C29H35NO2, mol. wt. = 429.60 g/mol  Physical properties: mp = 150oC. Specific rotation = +138.5o (c = 0.5 in chloroform). Mifepristone is a progesterone receptor antagonist with partial agonist activity. When used with prostaglandins, Mifepristone terminates pregnancy within the first 9 weeks of gestation. Structurally it is very similar to Norethindrone. The US patent is held by Rousell-UCLAF. Also known as RU-486 and Mifegyne.  Therapeutically it is used as an abortifacient.

Conformational Analysis Questions  

Qu 1:  

The energy diagram shows the relative energies of the conformations of 2,2,3-trimethylpentane produced during the rotation about the C3-C4 bond.  Match the structural representations provided to the appropriate points on the energy profile.

Qu 2:                                

 

There are four possible stereoisomers of 1-tert-butyl-3-methylcyclohexanes in which the cyclohexane is in a chair conformation.  The calculated heats of formation, ΔHf, of these four structures are listed to the right.

Draw the four possible structures.

Match the heats of formation, ΔHf,  values to the appropriate structures

Justify your choice.

Using the available data, calculate :

i) the heat of combustion, ΔHc,  of the most stable structure

ii) the equilibrium constant, K, for the interconversion of the two cis forms at 25oC.  

 

kcal/mol ΔHf (1) =  -38.16 ΔHf (2) =  -40.53 ΔHf (3) =  -44.41 ΔHf (4) =  -46.84 ΔHc (H2, gas) =  -68.0 ΔHc (C, graphite) =  -94.0

R = 1.987 cal/molK

kJ/mol

ΔHf (1) =   -159.66 ΔHf(2) =    -169.58 ΔHf (3) =   -185.81 ΔHf (4) =   -195.98 ΔHc (H2, gas) =  -284.51 ΔHc (C, graphite) =  -393.3 R = 8.314 J/molK

 

Qu 3: (tough)

                       

 

Cyclopropane is unique among the cycloalkanes in that it can be hydrogenated with H2 and Pt metal, giving propane.  Similarly, propene can be hydrogenated to give propane.

The heats of formation (ΔHf) for the hydrocarbons are:   propane = - 24.8 kcal/mol,    cyclopropane = + 12.8 kcal/mol , and   propene =  + 4.9 kacl/mol   You should recall that the ΔHf for the elements ( e.g. H2) is defined to be zero.

(1.)  From this data, calculate the heats of hydrogenation (ΔHh) of cyclopropane and propene.

(2.)  Show this data on a typical energy diagram in which the enthalpies of propene + H2, cyclopropane + H2 and propane are given in rough relative positions.

(3.)  The bond energy of a C-C single bond is about 83 kcal/mol, a C=C double bond is about 146 kcal/mol.  Using this data, together with the data from part (1), calculate a "ring strain" for cyclopropane, and compare this with the "ring-strain" value of 28 kcal/mol found experimentally from combustion data.

Answers ?

Conformational Analysis Answers  

Ans 1:              

First, as in any question you encounter with a compound name, draw out the compound (hence understanding nomenclature is vital). Using your model kit will also help solving this problem. It is convienient to describe the C3-C4 bond system as having a C3- and C4-methyl groups and a C3-t-butyl. In general terms, all the energy maxima will be eclipsed conformations, and the minima will be staggered. The highest energy conformation will be with the C3-t-butyl and C4-methyl groups eclipsed, B. Rotation will move to the least stable of the staggered conformers with the C4-methyl group gauche to both the C3-t-butyl and methyl groups, A. Further rotation gives the eclipsed conformer with the C3- and C4- methyls eclipsed, E, then onto the lowest energy conformation will be with these same two groups at 180o to each other, in the staggered conformation, D. Now to the most favourable eclipsed conformer with each of the R groups eclipsed only by H atoms, AB. The next staggered conformation has the C3-t-butyl group gauche to the C4-methyl group, C, and finally back to B.  

 

Ans 2:

The four structures are shown below along with their respective ΔHf values. The most stable conformation will have the most exothermic ΔHf and this will correspond to the situation

                                                                 

 

with both alkyl groups in the more favourable equatorial position. Equatorial substitutents are prefered over axial substituents due to the presence of the destabilising 1,3-diaxial interactions (a steric effect) when the substituent is axial due to its proximity to the other axial positions on the same face of the cyclohexane. The larger the substituent, the more destabilising this steric effect is. So the most stable isomer will be the one with both Me and tBu equatorial, then the one with the larger tBu equatorial and Me axial, then equatorial Me, axial tBu, and the both axial isomer will be the least stable. 

ΔHf = -46.84 ΔHf = -44.41 ΔHf = -40.53 ΔHf = -38.16 kcal/mol

ΔHf = -195.98 ΔHf = -185.81 ΔHf = -169.58 ΔHf = -159.66 kJ/molmost least stability

  The ΔHc of the most stable isomer can be calculated using the Hess's Law relationship for the balanced reactions shown to the left.  From the diagram we get the relationship that:  ΔHc  (elements) = ΔHf (isomer) +  ΔHc(isomer) So, based on the molecular formula, C11H22, we can insert the numbers to get : -1782 = -46.84 + ΔHc,  therefore ΔHc = -1735.16 kcal/mol. 

To calculate the equilibrium constant, we need to use the equation ΔG = -RT ln K and make the approximation that ΔG = ΔH, thus ΔG = -46.84 --38.16 = -8.68 kcal/mol  (for the two cis isomers).  Inserting the values,  -8680 cal/mol = -(1.987 cal/molK) (298 K) ln K, so K = 2.3 x 106

 

Ans 3:                

Here is a diagram showing the reactions and the data provided in the question:

                                                   

 

The heat of a reaction (in this case the heat of hydrogenation) can be calculated from the heats of formation of the products and starting materials (also see the figure below):

With this data, we can create the required energy diagram. If a C=C is 146 kcal/mol and a C-C is 83 kcal/mol, then we can estimate the strength of a π bond as 146 - 83 = 63 kcal/mol. This means a σ bond is 20 kcal/mol stonger than a π bond.  We need to compare the reactions of cyclopropane and propene to propane. The reaction of cyclopropane breaks a σ

bond and that of propene a π bond. Remember that breaking a bond requires an INPUT of energy and therefore, 20 kcal/mol more was required for cyclopropane compared to propene. But the ring strain of cyclopropane will be RELEASED on going to propane.

If we correct for the differing bonds, then the heat of hydrogenation of cyclopropane becomes -57.6 kcal/mol. (ie. more exothermic by 20 kcal/mol) Now we can get an estimate of the energy released due to ring strain by -57.6 - - 29.7 = -27.9 kcal/mol This compares very favourably with 28 kcal/mol found by combustion analysis.