I WANT SOME MOORE

Question 1

Racemic Switch = Chiral Switch

Answer 1

a drug that is already sold as a racemate is patented and sold as a single enantiomer

examples:

• Levomoprolol/Levotensin
• Dexfenfluramine/Isomeride
• Levodropropizine/Levotuss
• Ibuprofen/Serectil
• Levofloxacin/Cravit
• Barnidipine/Hypoca

Question 2

Why is drug chirality an important concept for future pharmacists and pharmaceutical scientists?

Answer 2

Drug metabolism

Defferent stereoisomers maybe metabolized through:

DIFFERENT MECHANISMS

DIFFERENT ENZYMES

have DIFFERENT METABOLITES

Question 3

Eutomer

Answer 3

More Potent enantiomer

with DESIRED ACTIVITY

Question 4

Distomer

Answer 4

LESS POTENT ENANTIOMER

with UNDESIRED activity

• an impurity (“isomeric ballast”)​*
• (-)-thalidomide = a TERATOGEN*
• chemical that can cause birth defects by adversely altering development of embryo or fetus without necessarily altering organism’s genetic structure.

Question 5

Eudismic Ratio

Answer 5

Eutomer / Distomer

High eudismic ratio when antagonist has stereogenic center in pharmacophore

Question 6

Why are receptors and drugs three-dimensional?

Answer 6

1. Bond length:
2. Bond angles:
3. Conformation: (torsion angle)
4. Hybridization:
5. Charges:
6. Size and nature of R group:
   * (hydrophobic, flexible, aromatic, polar)*

Question 7

Structure

Methods to determine & Related Terms

Answer 7

Complete Arrangement of all atoms of a molecule in space.

Determined by X-ray / Cryo-Em

Constitution

Configuration

Confirmation

Question 8

Constitution

Answer 8

Nature & Number of atoms

types of Bonds

manner at which they are linked = Connectivity

Formula SAME

Constitution Different

Question 9

Configuration

&

Isomer

Answer 9

Spatial arrangement of atoms that distinguishes molecules of the same CONSTITITION

Isomer = Same constitution, Different Configuration

Question 10

Conformation

Answer 10

Spatial Arrangement of atoms in a molecule of given

CONSTITUTION & CONFIGURATION

ROTATION about single bonds

&

Pyramidal Inversions at some atoms (ie. N)

>GIVE RISE TO DIFFERENT CONFORMATIONS

Question 11

Pyramidal Inversions

Answer 11

Change in Conformation (same consitution/configuration)

RAPID INTERCONVERSION

ex. Pyrimadal molecule like H-N-R₃

*Not considered a Chiral Center

Technically CHIRAL but the rapid interconversion makes it NOT ISOLABLE

Question 12

Chirality

Answer 12

Object that is

NOT SUPERIMPOSABLE ON ITS MIRROR IMAGE

Chirality is Removed if it acquires:

plane or center of symmetry

Can be chiral w/ symmetry of axis and none of the above

Question 13

Chiral Center

=

Asymmetric Center

=

Stereogenic Center

Answer 13

TETRAHYDRAL (sp³) atom

Four NON-equivalent atoms or groups attached to it

• *Sulfur or Phosphate tetrahydrals count (lone pair can be a group)*
• *Nitrogen groups without the pyramidial inversions too (ex. quiniquodine)*

Optically Active UNLESS:

Has Plane or Center of Symmetry

Question 14

σ Plane of Symmetry

Answer 14

Divides molecules so that

Points of one side of plane = Points on other side

by reflection through plane

ALWAYS ACHIRAL

Question 15

A-Chiral

Answer 15

IS SUPERIMPOSABLE ON ITS MIRROR IMAGE

Molecule w/ σ Plane of Symmetry = Achiral

Molecule w/ Center of Symmetry = Achiral

Molecule w/ Rotational Axis of Symmetry (C_n) MAY BE CHIRAL

Question 16

Center of Symmetry

“Point of Inversion”

*will be pointed out on test

Answer 16

Point from which ANY line drawn through the molecule

encounters identical environment in either direction from the center of symmetry

always ACHIRAL

*has chiral center but is ACHIRAL because of the center of symmetry

Question 17

AXIS of Symmetry

C_n

N-fold axis

Answer 17

Axis which rotates molecule around by 360* / n

such that the new position is indistinguishable from OG.

can be CHIRAL if:

NO OTHER SYMMETRY PROPERTIES

WITHOUT Center or Plane of symmetry

Question 18

Enantiomer

RR / SS

RS / SR

Answer 18

NON-Superimposable Mirror Images

type of stereoisomer

has to be CHIRAL

Enantiomers have EXACTLY the same energies

can’t be measured physically, EXCEPT by

OPTICAL ROTATION

(enantiomers rotate LIGHT in OPPOSITE directions)

Question 19

Fischer Projection

Answer 19

to help represent TETRAHYDRAL carbon w/ its 4 substituents

as a 2-D projection

1. Pretend there is a lightbulb on the left hand side
2. Light is shining to make a shadow
3. Pretend the shadow comes from the wedge projection

BADA BOOM A FISCHER PROJECTION

Question 20

Fischer Projection of Carbohydrates

Answer 20

Two in VERTICLE = going INTO the plane

(Carbonyl CHO & R Group)

Two in HORIZONTAL = going OUT TOWARDS YOU

Question 21

Newman Projection

Answer 21

for molecule with Two-Tetrahedral Centers

viewed along the C-C Axis

Question 22

Enantiopure

Answer 22

containing ONLY ONE enantiomer

Question 23

Racemate

=

Racemic Mixture

Answer 23

mixture that has EQUAL amounts of opposite enantiomers

50/50 mixture

*not meso (has single compound), racemate has mixture of enantiomers

Question 24

levo-rotatory (-)

&

dextro-rotatory (+)

little d & little l

Answer 24

Optically Active Enantiomers

l = (-) = rotate plane of polarized light to the left

d = (+) = “ to the right

CAN NOT BE DETERMINED

Question 25

Enantiomerismic Properties

Answer 25

_NOT distinguished by interactions with_: _ACHIRAL_ molecules (like _solvent_) _Physical properties_ measured by techniques (except polarized light) **Interact differently w/ other Entantiomeric molecules** **ex. Biological receptors**

Question 26

**Hybrid Drugs**

Answer 26

**Different Therapeutic Activities** ex. Propanalol **d-(+)-enantiomer = Vasodilation** *l-(-)-enantiomer = antihypertensive*

Question 27

CAPITAL **L / D** for **Carbohydrates**

Answer 27

Look @ stereocenter **FURTHEST away** from the **aldehyde / ketone** of the carbohydrate at the TOP. L = **-OH **GROUP ON LEFT **D** = **-OH ** GROUP ON **RIGHT** originated from glyceraldehyde \*carbohydrates are TYPICALLY = **D**

Question 28

**Erythrose** vs _Threose_

Answer 28

**Erythrose** = Two High Priorites on the **SAME SIDE** _Threose_ = Two high priorities on _Opposite Sides_

Question 29

CAPITAL **L / D** for **Amino Acids**

Answer 29

Look @ stereocenter **FURTHEST away** from the **Carboxylic acid** of the AA at the TOP. **L** = -**NH₂** GROUP ON **LEFT** D = -**NH₂** GROUP ON RIGHT \*Amino acids are TYPICALLY = **L**

Question 30

Cahn-Ingold-Prelog **(CIP****)** Rules ## Footnote **Clockwise = R** *Counter Clockwise = S*

Answer 30

Asign order by **atomic MASS/NUMBER** **Clockwise = R** * Counter Clockwise = S* - If first "sphere" is the same go to the NEXT - Double Bonds = Multiple Atoms =O \> -O x 2

Question 31

Order of **Atomic Masses** for presidence

Answer 31

**C \< N \< O \< F \< Cl \< (S) \< Br** **Lonepair \< Hydrogen \< D**

Question 32

Double Bond Geometry ## Footnote **Z / E**

Answer 32

**Ze same side** E = opposite **Z / E= DIASTERIOMER**

Question 33

Cyclic Compounds Geometry **Cis / Trans**

Answer 33

**Trans** = priorities are on **both on axial position** *_Ring flipped_= Trans are _both equitorial_* **Cis** = priorites are **axial / equatorial** *Ring Flipped = Still on axial and equatorial* ***Cis / Trans = DIASTERIOMER***

Question 34

**Diastereomers** E vs Z Cis vs Trans RR/RS , SS/RS , SS/SR

Answer 34

**stereoisomers** that _are not enantiomers​_ can have: **two+ Chiral Centers**, where not all chiral centers have opposite configuration ( ike **RR/RS , SS/RS , SS/SR**) **no chiral center(s) /** ***non-chiral*** just differ by spatial difference *(not related to mirror reflection)* ***E / Z** or* ***Cis / Trans***

Question 35

**Meso** Compounds

Answer 35

Have **chiral (assymetric) centers** but _ARE NOT CHIRAL_ **ACHIRAL** b/c **CONTAIN A PLANE OF SYMMETRY** (can have center of symmetry but not common) ex. mesoTartaric Acid * \*not a racemate (mixture of compounds), meso is a single compound*

Question 36

**Pseudo-Hybrid Drug**

Answer 36

**Multiple Isomeric Forms w/ different biologic activity** ex. Labetalol RR = eutomer for Beta Blocker S,R = eutomer for Alpha Blocker S,S / R,S = Inactive (isomeric Ballast)

Question 37

**EPIMER**

Answer 37

**Stereoisomers** thet differ by **ONLY ONE** **STEREOCENTER** still **_Diastereomers_** _if 2\> stereocenters_ *can be **enantiomers** & epimers if ONLY 1 stereocente*r

Question 38

Number of Stereoisomers

Answer 38

Number of Stereoisomers **= 2ⁿ** **n = # of stereocenters** Z/E COUNT TOO! * unless there are MESO compounds* * \<2ⁿ *

Question 39

**Torsion** **Angle** (or Dihedral)

Answer 39

The single parameter differentiated such conformers is the TORSION ANGLE **Angle between two planes** You look down the two atoms that are IN COMMON \*NEWMAN PROJECTION

Question 40

**synperi**-planar | (eclipsed)

Answer 40

**-30° to +30°** **sp** HIGH ENERGY

Question 41

**synclinal** | (gauche)

Answer 41

**+30° to +90°** **(+sc shown)** - 90° to -30° - sc as well

Question 42

**anticlinal** | (also eclipsed)

Answer 42

**+90° to +150°** **+ac (as shown)** - 150° to -90° - ac

Question 43

**antiperi**-planar | (trans/anti)

Answer 43

**+150° to -150°** **ap** *lowest energy*

Question 44

**Conformer**

Answer 44

**One set of stereoisomers** each characterized by a **Conformation** corresponding to a potential energy **Interconversion** of conformations = infinite number

Question 45

**Staggered Conformations**

Answer 45

**180°/ 60° / -60°** **Torsion angle** = groups are **AS FAR AWAY AS POSSIBLE** * \*typically have LOWEST potential energies* * local/global minimums*

Question 46

**Eclipsed Conformations**

Answer 46

**-120°/ 120° / 0°** **Torsion angle** between the 3 bonds = **ZERO** * \*typically have the HIGHER potential energy* * maximums*

Question 47

**Amide Bond** E / Z Conformation

Answer 47

**C-N bond acts like the Double Bond** *C-N bond is much shorter than a single bond* **(trans) Z is PREFFERED**, due to sterics *\*=O is the higher presidence group*

Question 48

**Ester Bonds** Cis (E) / Trans (Z) Conformation

Answer 48

**C-O bond acts like the Double Bond** *C-O bond is much shorter than a single bond* **(trans) Z is PREFFERED, due to sterics** *\*=O is the higher presidence group*

Question 49

Hydrogen Bonding on Conforormers

Answer 49

H-bonding can have a **LOCKING EFFECT** on conformation about C-C Bonds. Can overide unfavorable interactions \*synclinal interactions

Question 50

Why are all cyclic compounds **NONPLANAR**? | (except for 3-mem & aromatics)

Answer 50

**Baeyer Strain** Balance between valence bond angle strain Wants to be 109\* but to be flat it needs to be 120\* **Torsional Strain** If eclipsed (~flat) = torsional strain _If staggered (chair form) = tortional strain is relieved_

Question 51

6-Membered Ring Conformations

Answer 51

**Chair** -\> Half Chair (least favorable) -\>Twist -\> Boat -\> **Chair Flip**

Question 52

What does the rate & equilibrium of chair-chair transitions depend on? (6-membered rings)

Answer 52

–**Presence of heteroatoms(O,N,S,P**) instead of carbon atoms –**Steric size** of substituents –**Existence of interactions** which stabilize one particular conformer –Presence of **local dipoles** –**Stereoelectronic effects** (e.g. gauche effect, anomeric effect)

Question 53

Larger Substituants want to be placed in the ______ position Why?

Answer 53

**EQUITORIAL** Because of **SYNAXIAL REPULSION** **& sterics** **A-value** (conformational energy) = energy difference between the axial & equitorial positions

Question 54

5-Membered Systems

Answer 54

Envelope **Half Chair (MOST PREFFERED)** -substituant is in EQUITORIAL Envelope (ring flip) **Ring Pseudorotation / Conformational flux** much less ring strain, ring is constantly changing unlike 6mem

Question 55

**-30° to +30°** HIGH ENERGY

Answer 55

**synperi**-planar | (eclipsed)

Question 56

**+30° to +90°** **(shown)** -90° to -30°

Answer 56

**synclinal** | (gauche)

Question 57

**+90° to +150°** **(as shown)** -150° to -90°

Answer 57

**anticlinal** | (also eclipsed)

Question 58

**+150° to -150°** *lowest energy* "Global Minimum"

Answer 58

**antiperi**-planar | (trans/anti)