1 Conformational Analysis Towards Structural Biology Chem3D Embed - PDF document

Carey Chapter 3 – Conformations of Alkanes and Cycloalkanes Figure 3.5 – Energy distribution vs. Temp.  G =  H - T  S YSU YSU Conformational Analysis – Towards Structural Biology Cytosine (C) (from TGCA alphabet in DNA YSU YSU 1

Conformational Analysis – Towards Structural Biology « Chem3D Embed » Cytosine (C) (from TGCA alphabet in DNA YSU YSU Conformational Analysis – Towards Structural Biology « Chem3D Embed » YSU YSU 2

Conformational Analysis – Medicinal Chemistry Thymidine – incorporated into DNA as “T” Zidovudine (AZT) – incorporated into DNA instead of T – stops chain growth YSU YSU Conformational Analysis – Medicinal Chemistry « Chem3D Embed » YSU YSU 3

3.1 Conformational analysis of Ethane Since single bonds can rotate around the bond axis, different conformations are possible ‐ conformational analysis Figure 3.1 – Different representations of ethane ‐ ChemDraw YSU YSU 3.1 Conformational Depictions of Acyclic Molecules Different 3 ‐ D depictions of Ethane “Wedge/dash” “Newman” “Sawhorse” Rotation around the central C ‐ C bond will cause the hydrogens to interact ‐ rotamers or conformers YSU YSU 4

3.1 Definitions for Using Newman Projections Gauche Eclipsed Anti torsion angle 60 o torsion angle 0 o torsion angle 180 o Both gauche and anti conformers are staggered Eclipsed conformers are destabilized by torsional strain YSU YSU 3.1 – Conformational Analysis of Ethane Figure 3.4 – Rotation around the C ‐ C bond of Ethane YSU YSU 5

3.2 Conformational Analysis of Butane Figure 3.4 – Rotation around the C ‐ C bond of Ethane YSU YSU 3.3 Conformations of higher alkanes Anti Gauche eclipsed eclipsed (staggered) (staggered) Applicable for any acyclic molecule YSU YSU 6

3.4 Cycloalkanes – most are not planar YSU YSU 3.5 Cyclopropane and Cyclobutane Figure 3.10 – Depictions of Cyclopropane and Cyclobutane YSU YSU 7

3.6 Conformations of Cyclopentane Figure 3.12 – Important conformations of Cyclopentane YSU YSU 3.7 Conformations of Cyclohexane Conformationally flexible (without breaking bonds) Chair Boat Chair YSU YSU 8

3.7-3.8 Cyclohexane – axial and equatorial positions Figures 3.13 & 3.14 – Axial and Equatorial positions in cyclohexane chair and boat conformations YSU YSU 3.7-3.8 Cyclohexane – axial and equatorial positions « Chem3D Embed » YSU YSU 9

3.9 Conformational inversion – ring flipping Figure 3.18 – Energetics of the ring ‐ flip YSU YSU 3.10 Equilibrium constants for ring-flips Reactants Products Equilibrium Constant (K) = [Products] [Reactants]  G =  H – T  S  G = ‐ RTlnK YSU YSU 10

3.10 Equilibrium constants for ring-flips Left-Side Right-Side Equilibrium Constant (K) = [Right ‐ Side] [Left ‐ Side]  G = ‐ RTlnK K > 1, RHS favoured; K ~ 1, equal; K < 1, LHS favoured YSU YSU 3.10 Analysis of monosubstituted cyclohexanes  G = ‐ 0.24 Kcal/mol K = 1.5 YSU YSU 11

3.10 Analysis of monosubstituted cyclohexanes  G = ‐ 7.3 Kcal/mol K = 19 YSU YSU 3.10 Analysis of monosubstituted cyclohexanes  G = ‐ 8.6 Kcal/mol K = 32.3 YSU YSU 12

3.10 Analysis of monosubstituted cyclohexanes  G = ‐ 8.6 Kcal/mol K = 32.3 YSU YSU 3.10 Analysis of monosubstituted cyclohexanes  G = ‐ 22.8 Kcal/mol K = >9999 YSU YSU 13

3.10 Analysis of monosubstituted cyclohexanes  G = ‐ 22.8 Kcal/mol K = >9999 YSU YSU 3.10 Analysis of monosubstituted cyclohexanes Figure 3.19 YSU YSU 14

3.11 Disubstituted Cyclopropanes – Stereoisomers Figure 3.20 YSU YSU 3.12 Disubstituted Cycloalkanes - Stereoisomers Cis ‐ 1,2 ‐ dimethylcyclopropane is less stable than the trans isomer Cis ‐ 1,2 ‐ dimethylcyclohexane is less stable than the trans isomer Cis ‐ 1,3 ‐ dimethylcyclohexane is more stable than the trans isomer Cis ‐ 1,4 ‐ dimethylcyclohexane is less stable than the trans isomer All based on interactions between substituents and other groups on the ring YSU YSU 15

3.12 Disubstituted Cyclohexanes – Energy Differences YSU YSU YSU YSU 16

3.13 Medium and large rings - Cyclodecane « Chem3D Embed » YSU YSU 3.13 Medium and large rings - Erythromycin « Chem3D Embed » YSU YSU 17

3.13 Medium and Large Rings – YSU Chemistry O N N N O O O O N 2 Rh 2+ Ph O O O N O O O O N O O O YSU YSU Ph 3.14 Polycyclic Ring Systems adamantane YSU YSU 18

3.14 Polycyclic Ring Systems - Cholesterol cholesterol YSU YSU 3.14 Polycyclic Ring Systems - Bicyclics Bicyclobutane Bicyclo[2.1.0]pentane Bicyclo[3.2.0]heptane Bicyclo[4.1.0]heptane Bicyclo[2.2.2]octane Bicyclo[4.2.2]decane YSU YSU 19

3.15 Heterocyclic Compounds tetrahydrofuran pyrrolidine piperidine indole YSU YSU 3.15 Heterocyclic Compounds morphine ritilin librium YSU YSU 20

3.15 Heterocyclic Compounds - Carbohydrates OH O HO OH HO OH D ‐ Glucose (dextrose, blood sugar) YSU YSU 21