1. Organic Compounds: Cycloalkanes and Their Stereochemistry
Chapter 4
Organic Compounds:
Cycloalkanes and Their Stereochemistry
Suggested Problems -
1-21,28-31,35,37-8,41-3,45,58

2. Organic Compounds can be Open-Chained or Cyclic
We have discussed open-chained compounds up to this point
Many organic compounds contain rings of carbon atoms
e.g.
Prostaglandins
Steroids

3. Naming Cycloalkanes Cycloalkanes are saturated cyclic hydrocarbons
Have the general formula (CnH2n)

4. Mono-Substituted Cycloalkanes
The rules for naming cycloalkanes resemble the rules for naming alkanes.
In a cycloalkane with an attached alkyl substituent, the ring is the parent hydrocarbon unless the substituent has more carbons than the ring. In that case, the substituent is the parent hydrocarbon and the ring is named as a substituent.
There is no need to number the positiion of a single substituent on a ring.
A number is not needed.

5. Naming Di-substituted Cycloalkanes
1) Find the parent. # of carbons in the ring.
2) Name and number the substituents.

6. Di-Substituted Cycloalkanes
If the ring has two different substituents, they are listed in alphabetical order and the number-1 position is given to the substituent listed first.
Substituents are stated in alphabetical order.
Preference is to give #1 to first-listed substituent. But …..

7. Number Substituents to Achieve Lowest Possible Numbers
If there are more than two substituents on the ring, they are listed in alphabetical order, and the substituent given the number-1 position is the one that results in a second substituent getting as low a number as possible.
Maximize the low numbers!
If more than one name has the same low number,
choose the name with the next lowest number.

8. More Examples with Substituents
In the IUPAC system, alkyl halides are named as substituted alkanes. The prefixes for the halogens end with “o”.
Alkyl halides are also called haloalkanes.
List substituents alphabetically using smallest numbers.

9. Examples with Functional Groups
If the chain can be numbered in different ways to give the functional group the same number, the direction chosen is the one which then gives the substituent the lowest possible number.
The functional group is always assumed to be at the 1 position in a cyclic compound. In this instance the number for the functional group can be ignored.
Functional group gets lowest number. Listed as a suffix. Substituents on amines prefixed by “N”.

10. Cis-Trans Isomerism in Cycloalkanes
Cycloalkanes are less flexible than open-chain alkanes
Much less conformational freedom in cycloalkanes

11. Cis-Trans Isomerism in Cycloalkanes (Continued)
Because of their cyclic structure, cycloalkanes have 2 faces as viewed edge-on
“top” face “bottom” face
Therefore, isomerism is possible in substituted cycloalkanes
There are two different 1,2-dimethylcyclopropane isomers

12. Cis-Trans Isomerism in Cycloalkanes (Continued)
Stereoisomerism
Compounds which have their atoms connected in the same order but differ in 3-D orientation

13. Cis–Trans Isomers Cis–trans isomers result from restricted rotation.
Cyclic structures restrict rotation.
In cis-trans isomers, the atoms are connected similarly, but they are different in their arrangement in 3-dimensional space.
This slide shows cis-trans isomers resulting from substituents being on the same or opposite sides of a ring.
Note in the upper structures that the attachments appear identical – the difference is the bromide on the left jumps out of the plane toward you; the bromide on the right goes back behind the plane of the slide.
Cis-Trans Isomers are also referred to as geometric isomers; they result from restricted rotation caused by a cyclic structure or a double bond.
This slide shows some cyclic cis-trans isomers. Models show the two cyclobutanes are not the same compound.
In the case of cyclic structures – Cis isomers have their substituents on the same side of the ring; trans isomers have their substituents on opposite sides of the ring.
Cis: The substituents are on the same side of the ring.
Trans: The substituents are on opposite sides of the ring.

14. Bond Angles in Planar Cyclic Alkanes
Ideally, an sp3 carbon has bond angles of 109.5o.
Believing that all cyclic compounds were planar, an early chemist postulated that the deviation between the ideal bond angle for carbon (109.5) and the bond angle between carbons in planar cyclic structures (eg. 60o for cyclopropane) was a measure of angle strain. For example, the amount of angle strain in cyclopropane ( =49.5) was seen as a factor decreasing cyclopropane’s stabilty.

15. Stability of Cycloalkanes: Ring Strain
Rings larger than 3 atoms are not flat
Cyclic molecules can assume nonplanar conformations to minimize angle strain and torsional strain by ring-puckering
Larger rings have many more possible conformations than smaller rings and are more difficult to analyze

16. Stability of Cycloalkanes: The Baeyer Strain Theory
Baeyer (1885): since carbon prefers to have bond angles of approximately 109°, ring sizes other than five and six may be too strained to exist.
Rings from 3 to 30 C’s do exist but are strained due to bond bending distortions and steric interactions
Baeyer suggested that small and large rings might be too unstable to exist due to “angle strain” – the strain induced in a molecule when bond angles are forced to deviate from the ideal 109 degree tetrahedral value.
Strain can be measured through the heat of combustion of a molecule when compared with an unstrained (ie. acyclic) reference compound. Strain is measured per “CH2” unit.
Baeyer predicted that cyclopentane would be the most stable molecule because of its 108 degree bond angles. But the results suggest that cyclohexane has less ring strain and is lower in energy. Similarly, larger ring sizes are known to exist and have varying amounts of ring strain and varying strain energies.
Baeyer’s theory did not hold up because he assumed all cycloalkanes were flat. In fact most cycloalkanes are not flat and can adopt puckered three-dimensional conformations.

17. Types of Strain That Contribute to Overall Energy of a Cycloalkane
Angle strain - expansion or compression of bond angles away from most stable
Torsional strain - eclipsing of bonds on neighboring atoms
Steric strain - repulsive interactions between nonbonded atoms in close proximity

18. A Staggered Conformer is More Stable Than an Eclipsed Conformer
A molecule’s conformation changes from staggered to eclipsed millions of times per second at room temperature. As a result, the conformers cannot be separated from each other.
At any one time, approximately 99% of the ethane molecules will be in a staggered conformation because of the staggered conformer’s greater stability, leaving only 1% in less stable conformations.
The investigation of the various conformers of a compound and their relative stabilities is called conformational analysis.
The staggered conformer is more stable because of stabilizing interactions that take place between the C-H σ bonding molecular orbital on one carbon and the C-H σ* antibonding molecular orbital on the other carbon: the electrons in the filled bonding MO move partially into the unoccupied antibonding MO. Only in a staggered conformation are the two orbitals parallel, so staggered conformers maximize these stabilizing interactions.
The delocalization of electrons by the overlap of a σ orbital with an empty orbital is called hyperconjugation.

19. Angle Strain
tetrahedral bond angle = 109.5°
bond angle < 109.5°
The angle strain in cyclopropane can be understood by looking at the overlap of the orbitals that form the σ bonds. Normal σ bonds are formed by the overlap of two sp3 orbitals that point directly at each other.
In cyclopropane, the overlapping orbitals cannot point directly at each other, so the amount of overlap between them is less than in a normal C-C bond.
Decreasing the amount of overlap weakens the C-C bonds, and this weakness is what is know as angle strain.
Angle strain results from poor orbital–orbital overlap because
bonds have to deviate from the ideal (109.5°) bond angle.

20. Conformations of Cycloalkanes
Cyclopropane
3-membered ring must have planar structure
Symmetrical with C–C–C bond angles of 60°
Requires that sp3 based bonds are bent (and weakened)
All C-H bonds are eclipsed
In addition to the angle strain of the C-C bonds, all the adjacent C-H bonds in cyclopropane are eclipsed rather than staggered, making it even more unstable.

21. Cyclopropane
In addition to the angle strain of the C-C bonds, all the adjacent C-H bonds in cyclopropane are eclipsed rather than staggered, making it even more unstable.

22. Bent Bonds of Cyclopropane
In cyclopropane, the C-C bond is displaced outward from internuclear axis

23. Cyclobutane
Cyclobutane has less angle strain than cyclopropane but more torsional strain because of its larger number of ring hydrogens, and their proximity to each other
Cyclobutane is slightly bent out of plane - one carbon atom is about 25° above
The bend increases angle strain but decreases torsional strain

24. Cyclobutane Molecules twist out of a planar arrangement
If cyclobutane were planar, the bond angles would have to be compressed from 109.5o to 90o degrees.
Planar cyclobutane would therefore have less angle strain than cyclopropane because the bond angles in cyclobutane would be only 19.5o less than the ideal bond angle.
It would, however, have eight pairs of eclipsed hydrogens, compared with six pairs in cyclopropane.
Because of the eclipsed hydrogens, we will see that cyclobutane is not planar.
Molecules twist out of a planar arrangement
to minimize the number of eclipsed hydrogens.

25. Cyclopentane
Planar cyclopentane would have no angle strain but very high torsional strain
Actual conformations of cyclopentane are nonplanar, reducing torsional strain
Four carbon atoms are in a plane
The fifth carbon atom is above or below the plane – looks like an envelope

26. Cyclopentane
Baeyer predicted that cyclopentane would be the most stable of the cycloalkanes because its bond angles (108o) are closest to the ideal tetrahedral bond angle.
He also predicted that cyclohexane, with bond angles of 120o, would be less stable than cyclopentane and that the stability of cycloalkanes would continue to decrease as the number of sides in the cycloalkanes increased beyond six.
Baeyer was wrong, however. Cyclohexane is more stable than cyclopentane. Furthermore, cyclic compounds do not become less and less stable as the number of sides increases beyond six.
The mistake Baeyer made was in assuming that all cyclic molecules are planar.
The three carbons in cyclopropane must lie in a plane. The other cycloalkanes, however, twist and bend out of a planar arrangement in order to attain a structure that maximizes their stability by minimizing ring strain and the number of eclipsed hydrogens.
If cyclopentane were planar, it would have essentially no angle strain, but it would have 10 pairs of eclipsed hydrogens. Therefore, cyclopentane puckers, allowing some of the hydrogens to become nearly staggered.
However, in the process, the molecule acquires some angle strain.
The puckered form of cyclopentane is called the envellope conformation, because the shape of the ring resembles a squarish envelope with the flap up.
Molecules twist out of a planar arrangement to minimize angle strain and the number of eclipsed hydrogens.

27. Conformations of Cyclohexane
Substituted cyclohexanes occur widely in nature
The cyclohexane ring is free of angle strain and torsional strain
The conformation has alternating atoms in a common plane and tetrahedral angles between all carbons
This is called a chair conformation

28. Chair Conformer of Cyclohexane
The cyclic compounds most commonly found in nature contain six-membered rings because carbon rings of that size can exist in a conformation – called a chair conformation – that is almost completely free of strain.
All of the bond angles in a chair conformer are 111o (which is very close to the ideal tetrahedral angle) and all the adjacent bonds are staggered.
The chair conformer of cyclohexane is completely free of strain.
All bond angles are 111°and all adjacent bonds are eclipsed.

29. Listed in the table are the strain energies of a number of cycloalkanes. Notice cyclohexane is the most stable and cyclopropane and cylobutane are the least stable.

30. How to Draw Cyclohexane
Step 1 Draw two parallel lines, slanted downward and slightly offset from each other. This means that four of the cyclohexane carbons lie in a plane.
Step 2 Place the topmost carbon atom above and to the right of the plane of the other four, and connect bonds.
Step 3 Place the bottommost carbon atom below and to the left of the plane of the middle four, and connect the bonds. Note that the bonds to the bottommost carbon atom a parallel to the bonds to the topmost carbon.

31. Drawing the Chair Conformer
One should learn how to draw the chair conformation of cyclohexane. Start with two parallel lines then connect their ends with two V’s (the lower V being inverted).
Each carbon has an axial bond and an equatorial bond. The axial bonds are vertical and alternate above and below the ring.
The equatorial bonds point on a slant outward from the ring. Each equatorial bond is parallel to two ring bonds one bond away.
Notice that each equatorial bond is parallel to two ring bonds.

32. Axial and Equatorial Bonds
In this depiction, cyclohexane is viewed edge-on. The lower bonds of the ring are in front and the upper bonds are in back.

33. Axial and Equatorial Bonds in Cyclohexane
The chair conformation has two kinds of positions for substituents on the ring: axial positions and equatorial positions
Chair cyclohexane has six axial hydrogens perpendicular to the ring (parallel to the ring axis) and six equatorial hydrogens near the plane of the ring

34. Axial and Equatorial Positions
Each carbon atom in cyclohexane has one axial and one equatorial hydrogen
Each face of the ring has three axial and three equatorial hydrogens in an alternating arrangement

35. Conformational Mobility of Cyclohexane
Chair conformations readily interconvert, resulting in the exchange of axial and equatorial positions by a ring-flip

36. Ring Flip
Cyclohexane rapidly interconverts between two stable chair conformers because of the ease of rotation about its C-C bonds. This interconversion is called ring flip.
When the two chair conformers interconvert, bonds that are equatorial in one chair conformer become axial in the other chair conformer, and bonds that are axial become equatorial.
Cyclohexane interconverts between two stable chair conformers.

37. The Boat Conformer of Cyclohexane
Cyclohexane can also exist as a boat conformer. Like the chair conformer, the boat conformer is free of angle strain.
However, the boat conformer is not as stable because some of the C-H bonds are eclipsed.
The boat conformer is further destabilized by the close proximity of the σ– the hydrogens at the “bow” and” stern” of the boat- which cause steric strain.

38. Steric Strain

39. Conformers of Cyclohexane
The conformers that cyclohexane assumes when interconverting from one chair conformer to the other are shown in this slide.
To convert from the boat conformer to a chair conformer, one of the two topmost carbons of the boat conformer must be pulled down so that it becomes the bottommost carbon of the chair conformer.
When the carbon is pulled down just a little, the twist-boat conformer is obtained, which is more stable than the boat conformer because the flagpole hydrogens have moved away from each other, thus relieving some steric strain.
When the carbon is pulled down to the point where it is in the same plane as the side of the boat, the very unstable half-chair conformer is obtained. Pulling the carbon down farther produces the chair conformer.
This figure shows the relative energy of a cyclohexane molecule as it interconverts from chair conformer to the other. At room temperature, the two chair conformers are in rapid equilibrium.
Because the chair conformations are so much more stable than any of the other conformers, most molecules of cyclohexane are chair conformers at any given instant.
For every 10,000 chair conformers of cyclohexane, there is only one twist-boat conformer – the next most stable conformer.

40. Conformers of Monosubstituted Cyclohexanes
Unlike cyclohexane, which has two equivalent chair conformers, the two chair conformers of a monosubstituted cyclohexane are not equivalent.
The methyl substituent is in an equatorial position in one conformer and in an axial position in the other.
The chair conformer with the methyl substituent in an equatorial position is the more stable of the two conformers because a substituent has more room and, therefore, fewer steric interactions when it is in an equatorial position.

41. A Substituent is More Stable in an Equatorial Position
Note the steric interaction of the methyl group and two axial hydrogens in the conformation in b that are not present in the conformation in a.

42. 1,3-Diaxial Interactions
Any axial substituent will be relatively close to the axial substituents on the other two carbons on the same side of the ring because all three axial bonds are parallel to each other.
Because the interacting axial substituents are in 1,3-positions relative to each other, these unfavorable steric interactions are called 1,3-diaxial interactions.

43. Comparing Conformers Gauche is 0.9 kcal/mole less stable than anti.
A gauche conformer of butane and the axially substituted conformer of methylcyclohexane are compared here. Notice that the gauche interaction in butane is the same as a 1,3-diaxial interaction in methylcyclohexane.
We see that the gauche interaction between the methyl groups of butane causes a gauche conformer to be 0.9 kcal/mol less stable than the anti conformer.
Because there are two such interactions in the chair conformer of methylcyclohexane when the methyl group is in an axial position, this conformer is 1.8 kcal/mol less stable than the chair conformer with the methyl group in an equatorial position.
Because of the difference in stability of the two chair conformers, a sample of methylcyclohexane will, at any point in time, contain more chair conformers with the substituent in an equatorial position than with the substituent in an axial position.
Gauche is 0.9 kcal/mole
less stable than anti.
Axial is 1.8 (2 × 0.9) kcal/mol
less stable than equatorial.

44. Relationship to Gauche Butane Interactions
Gauche butane is less stable than anti butane by 3.8 kJ/mol because of steric interference between hydrogen atoms on the two methyl groups
The four-carbon fragment of axial methylcyclohexane and gauche butane have the same steric interaction
In general, equatorial positions give the more stable isomer

45. 1,3-Diaxial Interactions
Difference between axial and equatorial conformers is due to steric strain caused by 1,3-diaxial interactions
Hydrogen atoms of the axial methyl group on C1 are too close to the axial hydrogens three carbons away on C3 and C5, resulting in 7.6 kJ/mol of steric strain

46. Steric Strain in Monosubstituted Cyclohexanes

47. Conformations of Monosubstituted Cyclohexanes
Cyclohexane ring rapidly flips between chair conformations at room temp.
Two conformations of monosubstituted cyclohexane aren’t equally stable.
The equatorial conformer of methyl cyclohexane is more stable than the axial by 7.6 kJ/mol

48. The larger the substituent,
the more the equatorial-substituted conformer will be favored.
The relative amounts of the two chair conformers depend on the substituent.
The substituent with the greater bulk in the vicinity of the 1,3-diaxial hydrogens will have a greater preference for an equatorial position because it will have stronger 1,3-diaxial interactions.
The experimental equilibrium constant for the conformers of methylcyclohexane indicates that 95% of methylcyclohexane molecules have the methyl group in an equatorial position at room temperature.
Keq = [equatorial conformer]/[axial conformer] = 18/1
% equatorial conformer = [equatorial conformer]/ ([equatorial conformer] + [axial conformer]) X 100 = 18/(18+1) X 100 = 18/19 X 100 = 95%
Note the situation for tert-butylcyclohexane, where the 1,3-diaxial interactions are even more destabilizing because a tert-butyl group is larger than a methyl group.
Here 99.9% of the molecules have the tert-butyl group in an equatorial position.
Do the math as an example
DG = - RT ln Keq where R = J.K-1mol-1

49. The Only Difference Between Starch and Cotton
is an Equatorial Bond Versus an Axial Bond
Shown on this slide are structures for starch and for cellulose. Notice their difference in structure is merely an axial and an equatorial bond about one of the six-membered rings.
Humans have an enzyme which can break this bond in starch. They do not have an enzyme which can break break the bond in cellulose. However, some grazing animals do!

50. Conformations of Disubstituted Cylcohexanes
In disubstituted cyclohexanes the steric effects of both substituents must be taken into account in both conformations
There are two isomers of 1,2-dimethylcyclohexane. cis and trans
In the cis isomer, both methyl groups are on the same face of the ring, and the compound can exist in two chair conformations
Consider the sum of all interactions
In cis-1,2, both conformations are equal in energy

51. Trans-1,2-Dimethylcyclohexane
Methyl groups are on opposite faces of the ring
One trans conformation has both methyl groups equatorial and only a gauche butane interaction between methyls (3.8 kJ/mol) and no 1,3-diaxial interactions
The ring-flipped conformation has both methyl groups axial with four 1,3-diaxial interactions
Steric strain of 4  3.8 kJ/mol = 15.2 kJ/mol makes the diaxial conformation 11.4 kJ/mol less favorable than the diequatorial conformation
trans-1,2-dimethylcyclohexane will exist almost exclusively (>99%) in the diequatorial conformation

52. cis-1-tert-butyl-3-methylcyclohexane
This slide shows conformations of cyclohexanes that are substituted at C-1 and C-3 positions.
The molecule is 1-tert-butyl-3-methylcyclohexane.
Both substituents of the cis isomer are in equatorial positions in one chair conformer and both are in axial positions in the other.
The conformer with both substituents in equatorial positions is more stable.

53. trans-1-tert-butyl-3-methylcyclohexane
Both chair conformers of the trans isomer have one substituent in an equatorial position and the other in an axial position.
Because the tert-butyl group is larger than the methyl group, the 1,3-diaxial interactions will be stronger whenthe tert-butyl group is in an axial position.
Therefore, the conformer with the tert-butyl group in an equatorial position is more stable.

54. Cis and Trans Isomers
If a cyclohexane ring has two substituents, we must take both substituents into account when predicting which of the two chair conformer si more stable.
There are two different dimethylcyclohexanes. One has both substituents on the same side of the cyclohexane ring – it is called the cis isomer (latin – on this side).
The other has the two methyl substituents on opposite sides of the ring – it is called the trans isomer (Latin – across).
cis-1,4-Dimethylcyclohexane and trans 1,4-dimethylcyclohexane are examples of cis-trans isomers or geometric isomers.
Geometric isomer have the same atoms, and the atoms are linked in the same order, but they have different spatial arrangements.
The cis and trans isomer are different compounds with different melting and boiling points, so they can be separated from one another.

55. Each Disubstituted Isomer Has Two Chair Conformers
Every compound with a cyclohexane ring has two chair conformers; thus, both the cis isomer and the trans isomer of a disubstituted cyclohexane have two chair conformers.
The isomer at top left has one methyl group in an equatorial position and one methyl group in an axial position.
The conformer at top right also has one methyl group in an equatorial position and one methyl group in an axial position. Therefore both chair conformers are equally stable.
In contrast, the two chair conformers of trans-1,4-dimethylcyclohexane have different stabilities because one has both methyl substituents in equatorial positions and the other has both methyl groups in axial positions.
The conformer with both substituents in equatorial positions is more stable.

56. This Chair Conformer Has Four Diaxial Interactions
The chair conformer with both substituents in axial positions has four 1,3-diaxial interactions, causing it to be about 4 X 0.87 kcal/mol = 3.5 kcal/mol less stable than the chair conformer with both methyl groups in equatorial positions.
Thus almost all the molecules of trans-1,4-dimethylcyclohexane will be chair conformers with both substituents in equatorial positions.

57. Axial and Equatorial Relationships in Disubstituted Cyclohexanes

58. Conformations of Polycyclic Molecules
Decalin consists of two cyclohexane rings joined to share two carbon atoms (the bridgehead carbons, C1 and C6) and a common bond
Two isomeric forms of decalin: trans fused or cis fused
In cis-decalin hydrogen atoms at the bridgehead carbons are on the same face of the rings
In trans-decalin, the bridgehead hydrogens are on opposite faces
Both compounds can be represented using chair cyclohexane conformations
Flips and rotations do not interconvert cis and trans

59. Rings Can Be Trans Fused or Cis Fused
When two cyclohexane rings are fused – fused rings share two adjacent carbons – one ring can be considered to be a pair of substituents bonded to the other ring.
As with any disubstituted cyclohexane, the two substituents can be either cis or trans. The trans isomer (in which one substituent bond points upward the other downward) has both substituents in the equatorial position.
The cis isomer has one substituent in the equatorial position and on in the axial position. Trans-fused rings, therefore, are more stable than cis-fused rings.
trans-decalin
cis-decalin

60. The Steroid Ring System
Hormones are chemical messengers – organic compounds synthesized in glands and delivered by the bloodstream to target tissues in order to stimulate or inhibit some process.
Many hormones are steroids. Steroids have four rings designated here by A, B, C, and D. The B, C, and D rings are all trans fused, and in most naturally occurring steroids, the A and B rings are also trans fused.
The most abundant member of the steroid familyh in animals is cholesterol, the precursor of all other steroids.
Cholesterol is an important component of cell membranes.
Because its rings are locked in a specific conformation, it is more rigid than other membrane components.

61. Let’s Work a Problem
Draw two constitutional isomers of cis-1,2-dibromocyclopentane?

62. Answer
First, we need to understand what constitutional isomer means…the #’s of atoms, and types of atoms are the same, just the arrangement may be different. We have a 5 Carbon cyclic alkane, so we can only have a case when we have a 1,2- or a 1,3- dibromo linkage, as these links will be symmetrical with respect to middle carbon.