Lecture 4: Electronic Effects in Drugs Flashcards
Electronegativity
-most molecules have more than C
-non-Carbon atoms pull on sigma bond electrons to join them to C
Resonance
-overlapping p-orbitals allow atoms to share unshared electron pairs
Electronegativity effect on ionization
-stabilizes negative charge by withdrawing electrons
=more acidic
-effect weakens by going through multiple bonds
-addition to a central carbon gives greater effect
Acetic Acid less acidic than Chlorocetic acid less acidic than trichlorocetic acid
pKa: 4.76 > 2.87 > 0.64
Hammett’s sigma
-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
positive sigma value
-electron-WITHDRAWING group
-more acidic
-lower pKa (=SUBTRACT)
negative sigma value
-electron-DONATING
-less acidic
-higher pKa (=ADD)
Inductive effect
-withdrawing/donating electron density through sigma bond
-occurs in meta, ortho, and para
Resonance effect
-sharing lone pair electrons through pi bonds
-only occurs in ortho and para
Covalent bond
sharing electrons between two atoms
-sigma (head to head)
-pi (side by side)
Single bonds
-only have sigma bond
double bonds
-sigma and pi bonds both
-usually where resonance occurs
Electron-DONATING
-negative sigma value
-less acidic
Groups that DONATE inductively
-electrons ‘pushed’ through sigma bonds
-ex: alkyl groups
Groups that donate by resonance
-electrons shared in pi bonds
-unshared electron pair
-ortho/para directing
Groups that DONATE by resonance examples
-O-
-S-
-OCO-
-NH2
-NR2
-NHCO-
Electron WITHDRAWING groups
-positive sigma value
-more acidic
Groups that withdraw inductively
-electrons pulled through sigma bonds
-NO2, CN, COO-, CHO, X, O, S
Groups that withdraw electrons by resonance
-overlapping p-orbitals with electronegative groups (usually oxygen)
-ortho/para directing
-NO2, CN, CHO, COO-, SO2
Electron withdrawing groups mechanism
SLIDE 10
Which molecule is more acidic?
A. -COOH
B. -COOH, -Cl
the molecule with the -COOH and -Cl groups
Which molecule is more acidic?
A. -COOH
B. -COOH, -OCNH2
B
Electronic effects on basicity
-similar to effects on acid except reversed
-bases need electrons to bind H+
Electron donating groups (basicity)
-more basic
Electron withdrawing groups (basicity)
-less basic
Arylamines
-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)
Delaying metabolism
-natural enzymatic mods of molecules by the body
-polarity usually increased for excretion
p-hydrogen on aromatic ring
typically metabolically vulnerable
p-halogens
-frequently used as metabolism-resistant substituents
Haloperidol
-contains a p-fluorine that makes the molecule metabolically resistant
Isosteres
-H and F
-similar shape and electronic effects
Fluorine
-one of smallest atoms
-pi value = 0.14 (minimum change in logP)
-para value = 0.06 (minimum change in electronic effects)
van der waals radii
H= 1.2
F= 1.47
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
C. An electron‐donating group has a positive 𝜎 value.
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.
D. The resonance through the conjugated π bond system increases the basicity of the guanidino
group.
