Lecture 4: Electronic Effects in Drugs

Question 1

Electronegativity

Answer 1

-most molecules have more than C
-non-Carbon atoms pull on sigma bond electrons to join them to C

Question 2

Resonance

Answer 2

-overlapping p-orbitals allow atoms to share unshared electron pairs

Question 3

Electronegativity effect on ionization

Answer 3

-stabilizes negative charge by withdrawing electrons
=more acidic
-effect weakens by going through multiple bonds
-addition to a central carbon gives greater effect

Question 4

Acetic Acid less acidic than Chlorocetic acid less acidic than trichlorocetic acid

Answer 4

pKa: 4.76 > 2.87 > 0.64

Question 5

Hammett’s sigma

Answer 5

-describes effects of functional group based on their effect on the pKa of benzoic acid
-same group can be negative at one spot an positive at another

Question 6

positive sigma value

Answer 6

-electron-WITHDRAWING group
-more acidic
-lower pKa (=SUBTRACT)

Question 7

negative sigma value

Answer 7

-electron-DONATING
-less acidic
-higher pKa (=ADD)

Question 8

Inductive effect

Answer 8

-withdrawing/donating electron density through sigma bond
-occurs in meta, ortho, and para

Question 9

Resonance effect

Answer 9

-sharing lone pair electrons through pi bonds
-only occurs in ortho and para

Question 10

Covalent bond

Answer 10

sharing electrons between two atoms
-sigma (head to head)
-pi (side by side)

Question 11

Single bonds

Answer 11

-only have sigma bond

Question 12

double bonds

Answer 12

-sigma and pi bonds both
-usually where resonance occurs

Question 13

Electron-DONATING

Answer 13

-negative sigma value
-less acidic

Question 14

Groups that DONATE inductively

Answer 14

-electrons ‘pushed’ through sigma bonds
-ex: alkyl groups

Question 15

Groups that donate by resonance

Answer 15

-electrons shared in pi bonds
-unshared electron pair
-ortho/para directing

Question 16

Groups that DONATE by resonance examples

Answer 16

-O-
-S-
-OCO-
-NH2
-NR2
-NHCO-

Question 17

Electron WITHDRAWING groups

Answer 17

-positive sigma value
-more acidic

Question 18

Groups that withdraw inductively

Answer 18

-electrons pulled through sigma bonds
-NO2, CN, COO-, CHO, X, O, S

Question 19

Groups that withdraw electrons by resonance

Answer 19

-overlapping p-orbitals with electronegative groups (usually oxygen)
-ortho/para directing
-NO2, CN, CHO, COO-, SO2

Question 20

Electron withdrawing groups mechanism

Answer 20

SLIDE 10

Question 21

Which molecule is more acidic?

A. -COOH
B. -COOH, -Cl

Answer 21

the molecule with the -COOH and -Cl groups

Question 22

Which molecule is more acidic?

A. -COOH
B. -COOH, -OCNH2

Answer 22

B

Question 23

Electronic effects on basicity

Answer 23

-similar to effects on acid except reversed
-bases need electrons to bind H+

Question 24

Electron donating groups (basicity)

Answer 24

-more basic

Question 25

Electron withdrawing groups (basicity)

Answer 25

-less basic

Question 26

Arylamines

Answer 26

-unshared electron pair on the N participates in extended resonance with the aromatic pi bond system
-much less basic (pKa=4.6) than alipathic amines (not aromatic) (pKa=10.6)

Question 27

Delaying metabolism

Answer 27

-natural enzymatic mods of molecules by the body
-polarity usually increased for excretion

Question 28

p-hydrogen on aromatic ring

Answer 28

typically metabolically vulnerable

Question 29

p-halogens

Answer 29

-frequently used as metabolism-resistant substituents

Question 30

Haloperidol

Answer 30

-contains a p-fluorine that makes the molecule metabolically resistant

Question 31

Isosteres

Answer 31

-H and F
-similar shape and electronic effects

Question 32

Fluorine

Answer 32

-one of smallest atoms
-pi value = 0.14 (minimum change in logP)
-para value = 0.06 (minimum change in electronic effects)

Question 33

van der waals radii

Answer 33

H= 1.2
F= 1.47

Question 34

Which of the following statements is incorrect about Hammett’s 𝜎 values?

A. A group with a positive 𝜎 value increases the acidity.
B. A group with a positive 𝜎 value lower pKa .
C. An electron‐donating group has a positive 𝜎 value.
D. The 𝜎 value of the same group may vary according to their position

Answer 34

C. An electron‐donating group has a positive 𝜎 value.

Question 35

Guanabenz (shown below) is an α2‐adrenergic receptor agonist. Even though the drug has a
guanidino group, which normally has a pKa value around 11, the pKa value of guanabenz is 6.82.
Which of the following statements is NOT a reasonable explanation for the low pKa value of this
drug?

A. The lone pair electrons on nitrogen atoms in the guanidino group are shared through the
conjugated π bond system.
B. Sharing of the lone pair electrons with the aromatic ring by resonance reduces the electron
density of the guanidino group.
C. The two chloro groups inductively withdraw electrons through σ bonds.
D. The resonance through the conjugated π bond system increases the basicity of the guanidino
group.

Answer 35

D. The resonance through the conjugated π bond system increases the basicity of the guanidino
group.