4.1 Conformation of Ethane

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Ch.4 Stereochemistry of Alkanes and Cycloalkanes

stereochemistry: 3-dimensional aspects of molecules 4.1 Conformation of Ethane

conformation: the different arrangements of atoms that result from rotation about a single bond

conformers: a specific conformation (conformational isomer); same connections of atoms

H H H H C C rotate H H H H H C C HH H Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Sawhorse representation Newman projection

back carbon H H H C H HH front carbon H C H H HH H Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Energy barrier for rotation: not perfectly free rotation about σ-bonds

4 kJ/mol (1.0 kcal/mol) H HH HHrotate 60o H H H 4 kJ/mol H HH 4 kJ/mol H staggered conformation eclipsed conformation

rotational barrier: 12kJ/mol (2.9 kcal/mol) Ch.4 Stereochemistry of Alkanes and Cycloalkanes

- the 12 kJ/mol (2.9 kcal/mol) of extra energy present in the eclipsed conformation of ethane is called torsional strain

• Torsional strain is due to repulsion between electron clouds in the C-H bonds as they pass close by each other in the eclipsed conformer

H H HH

eclipsed conformation Ch.4 Stereochemistry of Alkanes and Cycloalkanes

A graph of potentiol energy versus bond rotation in ethane

HH HH H HH H

H H H H H HH H HH H H H HH H o o 0o 120o 240 360 gy r 12 kJ/mol Ene

o o 60o 180 300 H H H H H H H HH

H H H H H H H H H Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.2 Conformation of Propane

6 kJ/mol (1.4 kcal/mol)

CH3 H3CH H H rotate 60o H H H 4.0 kJ/mol H HH H 4.0 kJ/mol staggered conformation eclipsed conformation

rotational barrier: 14 kJ/mol (3.4 kcal/mol) Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.3 Conformation of Butane

CH3 CH3 H H H H H CH3 CH3 H3C H H H H H H CH3 H anti gauche

anti conformation: two large groups are in the opposite side

eclipsed conformations

gauche conformation: two large groups are 60o apart Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Eclipsed conformations

6.0 kJ/mol

H3CH

H C 6.0 kJ/mol 3H H H 4.0 kJ/mol

total cost: 16 kJ/mol (3.8 kcal/mol) eclipsed Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Eclipsed conformations

11 kJ/mol (2.6 kcal/mol)

H3CCH3

H H H 4.0 kJ/mol H 4.0 kJ/mol

total cost: 19 kJ/mol (4.6 kcal/mol) least stable eclipsed Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Gauche conformation: 3.8 kJ/mol (0.9 kcal/mol) unstable due to steric strain between two methyl groups

3.8 kJ/mol (0.9 kcal/mol) H H H H CH3 H CH3 H H H H H H H H gauche H

- hydrogen atoms on methyl groups interact

steric strain: repulsive interaction that occurs when atoms are too closer Ch.4 Stereochemistry of Alkanes and Cycloalkanes

CH3 CH3 Four possible H H H3C H conformations of n-butane H H HH CH3 H anti gauche

staggered

H C 3 H H3CCH3

H3C H H HH H HH

eclipsed eclipsed Ch.4 Stereochemistry of Alkanes and Cycloalkanes

A graph of potentiol energy versus bond rotation in buthane

Energy 19 kJ/mol 16 kJ/mol

3.8 kJ/mol

180o 120o 60o 0o 60o 120o 180o

CH 3 CH CH3 CH3 H CH 3 H3CCH HCH H H 3 3 3 H H3C H H CH3 H

H H H H3C HH H H H CH3 H H CH H HH H H HH H 3 H H CH3 anti gauche gauche anti Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Energy costs for interactions in alkane conformers

4.0 kJ/mol 6.0 kJ/mol (1.0 kcal/mol) (1.4 kcal/mol) HH H3CH

torsional strain mostly torsional strain

11 kJ/mol 3.8 kJ/mol (2.6 kcal/mol) (0.9 kcal/mol) CH3 H3CCH3 CH3

torsional + steric strain steric strain Ch.4 Stereochemistry of Alkanes and Cycloalkanes

• the most stable conformation of any alkanes has the C-C bonds in staggered arrangements and large substituents arranged anti to each other

HHHHHHHHHH

H H HHHH H H

zig-zag conformation

• At room temperature, enough thermal energy is present to cause rotation around σ-bonds to occur rapidly so that all conformations are in equilibrium. At any given time, however, a larger percentage of molecules will be found in a more stable conformation than in a less stable one. Ch.4 Stereochemistry of Alkanes and Cycloalkanes Practice Conformation of 1-chloropropane

Newman projections

H C 3 Cl

CH CH 3 3 H3CH H3CCl HHH Cl

H H H H H H H Cl H H Cl H HH Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.4 Stability of Cyclohexanes: The Baeyer Strain Theory

Angle strain (Baeyer strain): the strain induced in a molecule when a bond angle deviates from the ideal tetrahedral value

bond angles for hypothetical planar cycloalkane structures;

108o 120o o 60 90o

109o (tetrahedral angle) Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Heat of Combustion of Cycloalkanes ring strain: total energy of the compound- the energy of a strain-free reference compound heat of combustion: the amount of heat released when a compound burns completely with oxygen ; used for determination of starin energies of cycloalkanes ; the more energy (strained) a compound contains, the more energy (heat) is released on combistion

3n (CH ) + O nCO2 + nH2O + heat 2 n 2 2 Ch.4 Stereochemistry of Alkanes and Cycloalkanes cycloalkane strain energies, calculated by taking the difference between cycloalkane heat of combustion per CH2 and acyclic alkane heat of combustion per CH2, and multiplying by the number of CH2 units in a ring. Small and medium rings are strained, but cyclohexane ring is strain-free.

• the strain molecules (cyclopropane, cyclobutane) are unstable and highly reactive

• cyclopentane, cyclohexane are srtain free

o •medium rings C7-C13 are srtained: 115-120

• larger rings are unstrained ≥C14 Ch.4 Stereochemistry of Alkanes and Cycloalkanes cycloalkane strain energies Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.5 The Nature of Ring Strain

• rings are not flat; 3-dimensional conformations • torsional strain due to eclipsed C-H bonds in ring systems

The conformation of cyclopropane, showing the eclipsing of neighboring C-H bonds that give rise to torsional strain.

eclipsed H H H HH H

H H H H HH eclipsed Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Cycloalkanes adopt their minimum-energy conformation for the combination of three reasons:

• Angle strain: the strain due to expansion or compression of bond angles

• Torsional strain: the strain due to eclipsing of bonds on neighboring atoms

• Steric strain: the strain due to repulsive interactions when atoms approach each other too closely Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.6 Cyclopropane: An Orbital View colorless gas (bp= -33 oC); first prepared by reaction of sodium with 1,3- dibromopropane

2 Na Br Br + 2 Na Br

bent bond:

C C poor overlap C C C C 109o

A typical alkane C-C bond A bent cyclopropane C-C bond Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.7 Conformations of Cyclobutane and Cyclopentane Cyclobutane

less angle strain than cyclopropane but more torsional strain because of its larger number of ring hydrogens ; total strain of cyclobutane- 110.4 kJ/mol (26.4 kcal/mol) ; total strain of cyclopropane- 115 kJ/mol (27.5 kcal/mol) ; not flat but puckered → increase angle strain but decrease torsional strain

not quite eclipsed H H H H H H H H H H H H H H H H not quite eclipsed Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Cyclopentane total strain of cyclopentane- 26.0 kJ/mol (6.2 kcal/mol) ; not planar but envelop conformation

H H H H H H

H H H H envelop Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.8 Conformations of Cyclohexane

• unstrained

chair conformation: bond angle 111.5o (close to the ideal 109.5o tetrahedral angle)

H H H H H H H H CH2 H H H H H HCH2 H H H H H H

chair all staggered conformation Ch.4 Stereochemistry of Alkanes and Cycloalkanes

• drawing chair conformation: draw parallel three bonds pairs

this bond is in back

this bond is in front Ch.4 Stereochemistry of Alkanes and Cycloalkanes 4.9 Axial and Equatorial Bonds

H axial H H H H H equatorial H H H H H H

H H H H H

H H H H

top view Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.10 Conformational Mobility of Cyclohexane

ring-flip

the energy barrier for the ring flipping is small: fast ring flipping is observed ( two conformers are in fast equilibrium) Ch.4 Stereochemistry of Alkanes and Cycloalkanes

ring flipping

Br H ring-flip Br Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Hax Ea= 45 kJ/mol H Heq eq chair Hax

- rapid interconversion at 25 ℃

(Ea= 45 kJ/mol (10.8 kcal/mol), 20 kcal/mol available at 25 ℃)

-Hax and Heq are indistinguishable by 1H NMR at 25 ℃ o - at < -70 C, Hax and Heq are distinguishable by 1H NMR Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.11 Conformation of Monosubstituted Cyclohexanes

• two conformers of a monosubstituted cyclohexane are in fast equilibrium at room temperature but not equally stable

CH3 ring-flip CH3

∆ E = - RT ln K Ch.4 Stereochemistry of Alkanes and Cycloalkanes

CH3

CH3 ring-flip Ch.4 Stereochemistry of Alkanes and Cycloalkanes

A B

energy barrier vs rate constant

energy barrier at RT

5 kcal/mol 109 sec-1 10 kcal/mol 105 sec-1

15 kcal/mol 102 sec-1 > 20 kcal/mol Ch.4 Stereochemistry of Alkanes and Cycloalkanes

A B ∆ G = - RT ln K

free energy vs % of isomer

more stable free energy isomer(%) 1.0 kcal/mol 80% 1.3 kcal/mol 90% 2.3 kcal/mol 98% 4.1 kcal/mol >99.9% Ch.4 Stereochemistry of Alkanes and Cycloalkanes

1,3-diaxial interaction: steric strain, butane gauche interaction

CH H 3 H 7.6 kJ/mol H CH3 (1.8 kcal/mol)

7.6 kJ/mol ~ 95% equatorial methyl preference

Hax Hax Hax Heq Heq

Heq Heq H H ax ax CH3 Ch.4 Stereochemistry of Alkanes and Cycloalkanes butane gauche interactions 3.8 kJ/mol (0.9 kcal/mol) CH3 butane gauche H CH3

H H H

H H H H H CH3 H CH3 H CH3

1,3-diaxial interaction: butane gauche interaction (x2) 3.8 x 2 = 7.6 kJ/mol Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Steric Strain in Monosubstituted Cyclohexanes

R (kJ/mol) (kcal/mol) F 0.5 0.12 H Cl 1.0 0.25 X Br 1.0 0.25 OH 2.1 0.5

CH3 3.8 0.9 CH2CH3 4.0 0.95 CH(CH3)2 4.6 1.1 H C(CH3)3 11.4 2.7 C H 6.3 1.5 H X 6 5 COOH 2.9 0.7 CN 0.4 0.1 Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.12 Conformational Analysis of Disubstituted Cyclohexanes

• all steric interactions in both possible chair conformations must be analyzed

H CH3 H CH3 CH3 H CH3 H

CH3 CH3

1 gauche interaction (3.8 kJ/mol) 2 diaxial interaction (2 x 3.8 kJ/mol) total strain = 11.4 kJ/mol (2.7 kcal/mol) Ch.4 Stereochemistry of Alkanes and Cycloalkanes

H H CH CH 3 3 H CH3 H CH3 CH3 H H CH3 1 gauche interaction 4 diaxial interaction (3.8 kJ/mol) (15.2 kJ/mol) 11.4 kJ/mol more stable

trans-1,2-dimethylcyclohexane will exist almost exclusively (>99%: 2.7 kcal/mol) in the diequatorial conformation Ch.4 Stereochemistry of Alkanes and Cycloalkanes Practice Conformation of cyclohexane

CH3 CH CH CH3 3 3

CH3 CH3 more stable

CH CH3 3 CH3

CH3 CH3 CH3

equivalent Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Practice Conformation of cyclohexanes

Br Br more stable

Br Br

Br more stable Ch.4 Stereochemistry of Alkanes and Cycloalkanes Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.13 Boat Cyclohexane

H H

H H H H H H H H H H twist boat boat rel E = 23 kJ/mol (5.5 kcal/mol) rel E = 29 kJ/mol (7.0 kcal/mol) Ch.4 Stereochemistry of Alkanes and Cycloalkanes Ch.4 Stereochemistry of Alkanes and Cycloalkanes

Hax Ea= 45 kJ/mol H Heq eq chair Hax

twist boat half chair rel E = 23 kJ/mol rel E = 45 kJ/mol

rotational barrier Ch.4 Stereochemistry of Alkanes and Cycloalkanes

4.14 Conformations of Polycyclic Molecules

H trans-Decalin 0 kcal/mol H

H cis-Decalin + 2.2 kcal/mol H Ch.4 Stereochemistry of Alkanes and Cycloalkanes Ch.4 Stereochemistry of Alkanes and Cycloalkanes H

trans-decalin can adopt only one chair-chair conformation H

H H H H

cis-decalin can adopt two chair-chair conformations Ch.4 Stereochemistry of Alkanes and Cycloalkanes

CH3 H CH3 H

HH HO

Cholesterol (a steroid)

CH3 CH3

HO Ch.4 Stereochemistry of Alkanes and Cycloalkanes bridgehead carbon: carbon shared by two rings A 1-carbon bridge bridgehead carbons A 2-carbon bridge

Norbornane (Bicyclo[2.2.1]heptane

O Camphor Chemistry @Ch.4 Work StereochemistryMolecular of Alkanes Mechanics and Cycloalkanes

molecular mechanics: find the minimum energy conformations of molecules by mathematical calculations

Etotal = Ebond stretching + Eangle strain + Etorsional strain + Evan der Waals

- particularly useful in pharmaceutical research ; search the molecules which complementary fit with the receptor protein ; design the drug molecule and synthesis them