Deprotonation of NH, Deprotonation of CH, Deprotonation of Conjugate Acid

5
2
3

N1
H

Pyrrole
pKa: 23.0, 39.5

N1

N1
H

7
6
5

2
5

O1

Oxazole
pKa: 0.8

O1

Isoxazole
pKa: 3

8
3

N1

3
2

2
6

Quinoline
pKa: 4.92

N1

6
3
2

H
N

N3
N2

N1
H

5
6

5
6

7
8

Piperazine

N1

3
2N

Phthalazine

Pteridine

2
3
2

1,3,4-Thiadiazole
2-Imidazoline
pKa: 4.9

Imidazole
pKa: 6.9, 14.4, 33.7

HN
2

N1
H

3
5

Quinoxaline

SMe
3.6
4.4
6.0

S1

4
3
2

O1

1
5

O
O1

1,3-Dioxolane

O1

S1

H4
N
S1

2
5
6

Thiomorpholine

S1

4
3
2
1

1N

5
6

N7
H

Purine
pKa: 2.5, 8.9

N
H

S1

N 10
H

6
7
8
9

Phenoxazine

Christopher Lipinski (retired from Pfizer) formulated a set of

criteria fulfilled in most orally available drugs.
1. No more than five hydrogen bond donors.
2. No more than ten hydrogen bond acceptors.
3. A molecular weight under 500.
4. A LogP (partition coefficient) value under five.

Medicinal Chemistry Glossary:

4
5
6

1,4-Dithiane
5

3
2

H4
N
O1

N1

Pyridazine
pKa: 2.3

N1
H

1H-Indazole

Ph
4.5
4.8
5.5

vinyl
4.8
4.8
5.5

N
Me

Lipinski Rule of Five:

9
8

1,3,5-Trithiane

1,3-Dithiane
pKa: 31

N
2

CN
0.3
1.4
1.9

NO2
2.6
0.6
1.6

CH(OH)2
3.8
3.8
4.7
N

N
R

thermodynamic

N
H

S
N

kinetic

N
H

N
H

N
N

N1
H

3S

1,3,5-Triazine
pKa: <0

1,2,4-Triazole
pKa: 2.2, 10.3, 26.2

3
5

2
5

1,2,3-Oxadiazole

N
N

Phenothiazine
3

N1
H

Benzimidazole
pKa: 16.4

Pyrimidine
pKa: 1.3

N
N1

N1

Sites of Electrophilic Substitution: Major, Minor

Thiazole
pKa: 2.5, 29.4

N1
H

N 10
H

N1
H

1,2,3-Triazole
pKa: 9.3

1,4-Dioxane

N N

Cl
0.7
2.8
3.8

S1

5
5

Phenazine
OMe
3.3
4.9
6.6

Cinnoline

N10

Lithiation Positions: First, Second

N
Me

N
N

Tetrazole
pKa: 4.9

Imidazolidine

S1

N1
H

N1
H

4
5

N N

N1

N
3
3

1,2,4-Triazine
pKa: <0

N1

Quinazoline

Isothiazole
pKa: 0.5

Benzthiazole
pKa: 27.0

5
3

N
8

5
3

S1

Benzoxazole
pKa: 24.4

N1

N1

N1
H

Pyrazolidine

Effects of Substitution on Pyridine Basicity:

Me tBu NH2 NHAc
4
3
2-position 6.0 5.8
6.9
4.1
3-position 5.7 5.9
6.1
4.5
2
N1
4-position 6.0 6.0
9.2
5.9

1,8-Naphthyridine
pKa: 3.39

O1

5
6

N1
H

N2
1

Isoquinoline
pKa: 5.4

Tetrahydroquinoline
pKa: 5.0
4

Acridine
pKa: 5.6
3

S1

3
4

4H-Quinolizine

N10

3
4

5
6

N1
H

Pyrazine
pKa: 0.6

Thiophene
pKa: 33.0

Benzo[b]thiophene
pKa: 32.4

S1

Quinuclidine
pKa: 11.0

4H-Pyran

O1

Piperidine
pKa: 11.2

Pyridine
pKa: 5.2

8
3

2H-Pyran

Isobenzofuran

O1

Benzofuran
pKa: 33.2

O1

HN

5
6

2-Pyrazoline

N1
H

Indoline
pKa: 4.9
4

Indole
pKa: 21.0, 38.1

N1
H

Pyrazole
pKa: 19.8, 35.9

N1
H

7
2

Indolizine

2-Pyrroline

N1
H

Furan
pKa: 35.6

3H-Indole

7
5

N1

O1

3-Pyrroline 2H-Pyrrole

Isoindole

Carbazole
pKa: 19.9

N1
H

NH
7

3
2

N9
H

Pyrrolidine
pKa: 11.3,44

3
2

N1
H

Heterocyclic Chemistry

Essentials of Heterocyclic Chemistry-I

Baran, Richter

5
6

Morpholine
pKa: 8.4

N
H

Heterocyclic Aromaticity Values:

% (of PhH) -value
pyridine
tetrazole
pyrazole
quinoline
isoquinoline
pyrazine
1,2,5-triazole
pyrimidine
pyridazine

82
80
61
61
75
71
67
65

0.058

0.052
0.051
0.049

% (of PhH) -value

indole
benzothiophene
imidazole
pyrrole
benzofuran
thiophene
isoindole
furan
isobenzofuran

43
37
45

0.047
0.044
0.042
0.039
0.036
0.032
0.029
0.007
0.002

0.049
12
ED50: Dose required to yield maximum therapeutic effect in 50%
of test animals.
Efficacy: Description of the relative intensity with which agonists
vary in the response they produce, even with similar affinity.
Homologue: A compound belonging to a series of compounds differing from each other by a repeating unit (i.e. a CH2, a peptide residue, etc.).
Intrinsic activity: The maximal stimulatory response induced by a compound relative to that of a given reference comopund.
LD50: Dose required to kill 50% of test animals.
Partition coefficient (LogP): Log10 of the ratio of a compound's concentration in 1-octanol vs. water at equilibrium. A LogP<0 means that
a compound is more soluble in water than in 1-octanol.
Pharmacophore: The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a
specific biological target structure and to trigger (or block) its biological response. This is not a real molecule or moiety, but rather an
abstract concept that is considered the largest common denominator shared by a set of active molecules.
Potency: The dose of a drug required to produce a specific effect of given intensity as compared to a standard reference.
Therapeutic index: LD50/ED50

Essentials of Heterocyclic Chemistry-I

Baran, Richter
Indoles:

R'
R'

O
R'

NH2

N
H

Fischer Indole Synthesis

S
N
H

NHR

N
H

[H]

DMAD

N+

Ph

R1

BrMg

R'

i. DMFDMA

NO2

ii. Pd/C, H2

Me

H2NNH2

R
N
H

ii. H+

Base

N
R1

R2

R2

R2
N
R1

Madelung Indole Synthesis

R
H+

CO2H
N
H

NH2

Ph

Ph

N
H

OH

i. DMAD,
piperidine

CO2Me

HS

CO2Me

ii. NaOMe

S
MeO2C
Fiesselmann Thiophene Synthesis

Ph

Ph

R1

S
HO2C
Hinsberg Thiophene Synthesis

CN

CO2H

ii. acid

N
R3

i. LA

Cl

OH
N
H

ii. NaBH4

R1

i. S8

NH2

ii. Amine

S
R2
Gewald Aminothiophene Synthesis

R2

N
H

X = halide

CuOTf
NH2

Castro Indole Synthesis

CO2R

Cl

H+
CO2R

Hemetsberger Indole Synthesis

N
H

Ni0

N
R
Mori-Ban Indole Synthesis

K2CO3

N
H

R''

CO2X

R
R'

R
R1

R2

Ph

OH

O
N

O
N

N
R

R''

van Leusen Oxazole Synthesis

R'

TosMIC

R'
Robinson-Gabriel Oxazole Synthesis

N
H

Bischler Indole Synthesis

CHO
R'

HCl

CN

R'CHO

Fisher Oxazole Synthesis

Me

N3

R1

R1

Hantzsch Pyrrole Synthesis

Me

i. NaOEt,
S(CH2CO2Et)2

R2

Ar
H+

Ar

H2N

Br

O
Paal Thiophene Synthesis

Sugasawa Indole Synthesis

R2

R2

N
H

Et

Me

HO

R1

CN

+
NH2

Reissert Indole Synthesis

CO2Me
N
H

Oxazoles and Isoxazoles:

R
ii. [H],

OMe
Zn

Nenitzescu Indole Synthesis

i. (CO2Et)2,
Base
NO2

Me

P4S10

Me

Me

R1
R3HN

CoI2,

Graebe-Ullmann Carbazole Synthesis

HOAc
MeO2C

O
N
H

R3
O

Piloty Pyrrole Synthesis

X = OH, NH2

R3

N
R

Thiophenes:

N
N

Bucherer Carbazole Synthesis

CO2Me

MeO2C

Et

Me

Batcho-Leimgruber Indole Synthesis

HN

R'

Boger Pyrrole Synthesis

N
i. PhNHNH2
NaHSO3,

N
H

Paal-Knorr Pyrrole Synthesis

N
R

PdII

R
Bartoli Indole Synthesis
X

RNH2

N
R

X
R

RNH2

R'

MeO

N
H

R1

Me

O
X
Knorr Pyrrole Synthesis

Huisgen Pyrrole Synthesis

R''

R'

Me

R2

NH2

Ph

R2
NO2

CO2Me

Larock Indole Synthesis

Hegedus Indole Synthesis

CO2X

CO2Me

COY

N
H
Barton-Zard Pyrrole Synthesis

N
R

Pd(OAc)2,
base

NHR

R'

R'

O-

R''

R'

I
Me

CO2X

base

R'

Gassman Indole Synthesis

PdII;

CN

R'

iii. base
iv. Raney-Ni, H2

N
H

NO2

R'
O

Fukuyama Indole Synthesis

NH2

Pyrroles:

N
R

i. tBuOCl
ii.Me
S

Me

AIBN

N
R

N
R

N
H

nBu SnH
3

PdII

acid,

R'

R'
Pd0

Heterocyclic Chemistry

NH2OH

R'
N

O
R
Claisen Isoxazole Synthesis

O
R2

N
O

Cornforth Rearrangement

R1

HN
R

CO2H
O

Ac2O
R

O
O

Erlenmeyer-Plchl Azlactone Synthesis