4. Organic Compounds: Cycloalkanes and their Stereochemistry Why this chapter? Because cyclic molecules are commonly encountered in all classes of biomolecules: - Proteins - Lipids - Carbohydrates - Nucleic acids

2 We’ve discussed open-chained compounds up to this point Most organic compounds contain rings of carbon atoms e.g. - Prostaglandins - Steroids

3 Cycloalkanes Cycloalkanes Are cyclic alkanes. (C n H 2n ) Have 2H fewer than the open chain. (C n H 2n ) Are named by using the prefix cyclo- before the name of the alkane chain with the same number of carbon atoms.

4 4.1 Naming Cycloalkanes Cycloalkanes are saturated cyclic hydrocarbons Have the general formula (C n H 2n )

5 Cycloalkanes The structural formulas of cycloalkanes are usually represented by geometric figures, Cyclopropane Cyclobutane Cyclopentane Cyclohexane

6 Naming Cycloalkanes Find the parent. # of carbons in the ring. Number the substituents

7 Naming Cycloalkanes

8 Learning Check Name each of the following: 1. CH 3 CH 2 ─ CH 3 2. Cl

9 1. CH 3 CH 2 ─ CH 3 2. Cl Solution Name each of the following: methylcyclopropane 1-chloro-3-ethylcyclohexane

What is the IUPAC name for the following molecule? 1. 1-(2-methylbutyl)cyclopentane 2. 2-(3-methylbutyl)cyclopentane 3. 2-(2-methylbutyl)cyclopentane 4. (1,2-dimethylpropyl)cyclopentane 5. (2,2-dimethylpropyl)cyclopentane Learning Check

What is the IUPAC name for the following molecule? 1. 1-(2-methylbutyl)cyclopentane 2. 2-(3-methylbutyl)cyclopentane 3. 2-(2-methylbutyl)cyclopentane 4. (1,2-dimethylpropyl)cyclopentane 5. (2,2-dimethylpropyl)cyclopentane Solution

How many secondary hydrogens are there in the cycloalkane shown below? Learning Check

How many secondary hydrogens are there in the cycloalkane shown below? Solution

Cis-Trans Isomerism in Cycloalkanes Cycloalkanes are less flexible than open-chain alkanes Much less conformational freedom in cycloalkanes (can’t rotate around single bonds)

15 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-dimethyl-cyclopropane isomers Cis-Trans Isomerism in Cycloalkanes

16 Stereoisomerism Compounds which have their atoms connected in the same order but differ in 3-D orientation

Glucosamine (R = H), a naturally occurring substance found in the exoskeleta of marine invertebrates, is believed by some to be helpful in relieving arthritic symptoms in humans. What are, respectively, the relative positions of the amino group to the CH 2 OH substituent and OR group? 1. cis, cis 2. trans, trans 3. cis, trans 4. trans, cis 5. cannot be determined from this kind of perspective drawing Learning Check

Glucosamine (R = H), a naturally occurring substance found in the exoskeleta of marine invertebrates, is believed by some to be helpful in relieving arthritic symptoms in humans. What are, respectively, the relative positions of the amino group to the CH 2 OH substituent and OR group? 1. cis, cis 2. trans, trans 3. cis, trans 4. trans, cis 5. cannot be determined from this kind of perspective drawing Solution

4.3 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

20 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

21 Summary: Types of Strain 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

Conformations of Cycloalkanes Cyclopropane 3-membered ring must have planar structure Symmetrical with C–C–C bond angles of 60° Requires that sp 3 based bonds are bent (and weakened) All C-H bonds are eclipsed

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

24 Cyclobutane Cyclobutane has less angle strain than cyclopropane but more torsional strain because of its larger number of ring hydrogens Cyclobutane is slightly bent out of plane - one carbon atom is about 25° above ◦ The bend increases angle strain but decreases torsional strain

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

What kind of strain is relieved the most by ring puckering in cyclopentane? 1. torsional 2. steric 3. angle 4. steric and angle 5. torsional and steric Learning Check

What kind of strain is relieved the most by ring puckering in cyclopentane? 1. torsional 2. steric 3. angle 4. steric and angle 5. torsional and steric Solution

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

29 How to Draw Cyclohexane

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

31 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

32 Drawing the Axial and Equatorial Hydrogens

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

Which of the following does not contribute to the overall energy of a cycloalkane? 1. torsional strain 2. angle strain 3. hydrogen bonding 4. steric strain 5. All of these contribute to the overall energy of a cycloalkane. Learning Check

Which of the following does not contribute to the overall energy of a cycloalkane? 1. torsional strain 2. angle strain 3. hydrogen bonding 4. steric strain 5. All of these contribute to the overall energy of a cycloalkane. Solution

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

37 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 C 1 are too close to the axial hydrogens three carbons away on C 3 and C 5, resulting in 7.6 kJ/mol of steric strain 2 x 3.8 = 7.6

38 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 more stable isomer

Conformational Analysis of Disubstituted Cyclohexanes 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 compound can exist in two chair conformations

Cis 1,2-Dimethylcyclohexane Consider the sum of all interactions In cis-1,2, both conformations are equal in energy 2 x 3.8 = = 11.4 kJ

41 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 42 Trans-1,2-Dimethylcyclohexane 2 x 3.8 = = 15.2 kJ

Table 4-1, p. 124

44 Cis-1-t-butyl-4-chlorocyclohexane 2 x 1.0 = x 11.4 = 22.8

p. 126 OH’s preferred Equatorial (Haworth Projection)

Which of the above molecules represents the most stable conformation of trans-1,3-dimethylcyclohexane? 1. a 2. b 3. c 4. d 5. e Learning Check

Which of the above molecules represents the most stable conformation of trans-1,3-dimethylcyclohexane? 1. a 2. b 3. c 4. d 5. e Solution

Which of the following statements is true? 1. An axial group encounters more steric strain than an equatorial group. 2. All substituted cycloalkanes possess axial and equatorial bonds. 3. Only cyclopentane rings possess axial and equatorial bonds. 4. Cyclohexane derivatives are more stable with axial substituents than with equatorial substituents. 5. A cyclic compound cannot contain a double bond. Learning Check

Which of the following statements is true? 1. An axial group encounters more steric strain than an equatorial group. 2. All substituted cycloalkanes possess axial and equatorial bonds. 3. Only cyclopentane rings possess axial and equatorial bonds. 4. Cyclohexane derivatives are more stable with axial substituents than with equatorial substituents. 5. A cyclic compound cannot contain a double bond. Solution

Which of the following statements is true concerning the isomers cis-1,2-dimethylcyclohexane and cis-1,3- dimethylcyclohexane? 1. They are not constitutional isomers. 2. They represent different conformations of the same molecule. 3. The favored conformer of the 1,3-isomer is more stable than that of the 1,2-isomer. 4. The favored conformer of the 1,3-isomer and that of the 1,2- isomer are equal in energy. 5. The relative stability of the two molecules cannot be determined. Learning Check

Which of the following statements is true concerning the isomers cis-1,2-dimethylcyclohexane and cis-1,3- dimethylcyclohexane? 1. They are not constitutional isomers. 2. They represent different conformations of the same molecule. 3. The favored conformer of the 1,3-isomer is more stable than that of the 1,2-isomer. 4. The favored conformer of the 1,3-isomer and that of the 1,2- isomer are equal in energy. 5. The relative stability of the two molecules cannot be determined. Solution

What isomer of dichlorocyclohexane is represented by the Newman projection shown below? 1. 1-axial; 3-axial 2. 1-equatorial; 4-equatorial 3. 1-equatorial; 3-equatorial 4. 1-equatorial; 3-axial 5. 1-equatorial; 4-axial Learning Check

What isomer of dichlorocyclohexane is represented by the Newman projection shown below? 1. 1-axial; 3-axial 2. 1-equatorial; 4-equatorial 3. 1-equatorial; 3-equatorial 4. 1-equatorial; 3-axial 5. 1-equatorial; 4-axial Solution

Which of the above structures represents the most stable conformation of 1-tert-butyl-3,5-dimethylcyclohexane? 1. a 2. b 3. c 4. d 5. e Learning Check

Which of the above structures represents the most stable conformation of 1-tert-butyl-3,5-dimethylcyclohexane? 1. a 2. b 3. c 4. d 5. e Solution

What is the energy difference between the two chair conformations of trans-1,2-dimethylcyclohexane? 1. zero 2. one gauche interaction 3. two gauche interactions 4. three gauche interactions 5. four gauche interactions Learning Check

What is the energy difference between the two chair conformations of trans-1,2-dimethylcyclohexane? 1. zero 2. one gauche interaction 3. two gauche interactions 4. three gauche interactions 5. four gauche interactions Solution

What happens to a substituent in a chair conformation of cyclohexane when all bonds rotate in a synchronized fashion? 1. nothing, it stays where it was 2. it “flips” to an alternative position on the same carbon 3. it moves to the next carbon 4. the carbon to which the substituent is attached changes hybridization 5. it moves from a cis to a trans position Learning Check

What happens to a substituent in a chair conformation of cyclohexane when all bonds rotate in a synchronized fashion? 1. nothing, it stays where it was 2. it “flips” to an alternative position on the same carbon 3. it moves to the next carbon 4. the carbon to which the substituent is attached changes hybridization 5. it moves from a cis to a trans position Solution

Dipole moments usually are measured on collections of molecules, and represent average values for all conformations present. Which of the following collections of molecules will not show a dipole moment? 1. 1,2-dibromoethane 2. trans-1,2-dibromocyclohexane 3. cis-1,2-dibromocyclohexane 4. cis-1,4-dibromocyclohexane 5. trans-1,4-dibromocyclohexane Learning Check

Dipole moments usually are measured on collections of molecules, and represent average values for all conformations present. Which of the following collections of molecules will not show a dipole moment? 1. 1,2-dibromoethane 2. trans-1,2-dibromocyclohexane 3. cis-1,2-dibromocyclohexane 4. cis-1,4-dibromocyclohexane 5. trans-1,4-dibromocyclohexane Solution

Which of the above will have the highest energy after the chair flip? 1. a 2. b 3. c 4. d 5. e Learning Check

Which of the above will have the highest energy after the chair flip? 1. a 2. b 3. c 4. d 5. e Solution

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

65

Fig. 4-17, p. 128

p. 136 Cholesterol Steroids

p. 129

p. 135

What are the relative geometries of ring fusions (starting from the left) for the steroid shown below? 1. cis, cis, cis 2. cis, cis, trans 3. cis, trans, trans 4. trans. cis, cis 5. trans, trans, cis Learning Check

What are the relative geometries of ring fusions (starting from the left) for the steroid shown below? 1. cis, cis, cis 2. cis, cis, trans 3. cis, trans, trans 4. trans. cis, cis 5. trans, trans, cis Solution