Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid
3
4
5
4
3
6
4
4
3
5
2
3
5
2
5
N1
H
Pyrrole
pKa: 23.0, 39.5
3
4
3
2
5
4
4
2
2
5
4
3
5
4
O
2
6
N1
3
5
2
6
N1
H
7
9
7
6
5
2
2
5
O1
Oxazole
pKa: 0.8
N
4
N
5
5
6
O1
Isoxazole
pKa: –3
N
5
7
2
8
3
7
2
N
N1
3
3
2
2
6
Quinoline
pKa: 4.92
N
2
7
N1
6
3
2
H
N
N3
N2
N1
H
5
6
5
6
7
8
Piperazine
N1
3
2N
1
Phthalazine
4
2
4
8
Pteridine
7
N
4
3
4
N
2
2
3
2
1,3,4-Thiadiazole
2-Imidazoline
pKa: –4.9
5
Imidazole
pKa: 6.9, 14.4, 33.7
3
3
4
HN
2
2
5
N1
H
3
5
2
2
Quinoxaline
SMe
3.6
4.4
6.0
S1
4
3
2
2
4
O1
1
5
S
5
N
S
N
5
O
O1
1,3-Dioxolane
2
O1
4
S1
4
H4
N
S1
2
5
6
Thiomorpholine
5
S1
3
N
2
4
N
O
O
S
4
3
2
1
O
1N
5
6
N7
H
Purine
pKa: 2.5, 8.9
N
H
S
N
S1
N 10
H
6
7
8
9
Phenoxazine
S
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
5
8
6
N
2
5
3
2
H4
N
O1
6
N1
Pyridazine
pKa: 2.3
N1
H
7
9
1H-Indazole
Ph
4.5
4.8
5.5
vinyl
4.8
4.8
5.5
R
S
N
Me
S
Lipinski Rule of Five:
9
8
4
S
2
1,3,5-Trithiane
6
1,3-Dithiane
pKa: 31
6
7
N
2
3
CN
–0.3
1.4
1.9
S
NO2
–2.6
0.6
1.6
CH(OH)2
3.8
3.8
4.7
N
N
R
thermodynamic
N
H
5
3
4
6
3
S
N
kinetic
N
O
N
N
H
O
N
H
N
N
N
N1
H
5
S
2
3S
N
4
1,3,5-Triazine
pKa: <0
N
1,2,4-Triazole
pKa: 2.2, 10.3, 26.2
S
9
3
5
2
5
1,2,3-Oxadiazole
8
4
2
N
N
3
Phenothiazine
3
2
N1
H
N
6
N
3
Benzimidazole
pKa: 16.4
4
5
Pyrimidine
pKa: 1.3
5
N
N1
6
N1
Sites of Electrophilic Substitution: Major, Minor
Thiazole
pKa: 2.5, 29.4
N1
H
7
3
3
7
N 10
H
N1
H
2
5
R
5
2
1,2,3-Triazole
pKa: 9.3
6
6
1,4-Dioxane
N N
N
6
6
Cl
0.7
2.8
3.8
2
N
S1
5
5
4
N
4
N
1
3
5
Phenazine
OMe
3.3
4.9
6.6
3
2
Cinnoline
N10
1
N
8
Lithiation Positions: First, Second
N
Me
4
N
2
4
4
N
N
4
Tetrazole
pKa: 4.9
Imidazolidine
3
2
S1
N1
H
N1
H
O
3
4
5
5
4
N
N N
N
4
N1
N
3
N
3
3
3
7
1,2,4-Triazine
pKa: <0
4
N1
N
4
6
Quinazoline
5
S
Isothiazole
pKa: –0.5
Benzthiazole
pKa: 27.0
6
5
3
N
8
5
3
N
4
6
N
4
S1
7
Benzoxazole
pKa: 24.4
3
4
6
8
4
N1
N1
N1
H
Pyrazolidine
4
N
5
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
4
3
O1
7
5
6
2
N1
H
2
5
N2
1
Isoquinoline
pKa: 5.4
3
Tetrahydroquinoline
pKa: 5.0
4
3
4
N
3
8
4
8
Acridine
pKa: 5.6
3
5
S1
4
7
3
4
4H-Quinolizine
7
N10
5
6
6
3
4
2
N
6
8
2
5
6
N1
H
N
4
Pyrazine
pKa: 0.6
5
Thiophene
pKa: 33.0
Benzo[b]thiophene
pKa: 32.4
1
8
4
2
S1
7
5
Quinuclidine
pKa: 11.0
1
6
4H-Pyran
7
1
2
6
O1
3
5
5
2
9
4
N
2
Piperidine
pKa: 11.2
Pyridine
pKa: 5.2
6
8
3
5
3
2H-Pyran
Isobenzofuran
4
3
O1
1
7
Benzofuran
pKa: 33.2
4
2
6
O1
7
5
2
N
HN
5
5
6
5
4
2
8
3
3
N
3
4
2-Pyrazoline
N1
H
7
Indoline
pKa: 4.9
4
5
Indole
pKa: 21.0, 38.1
N1
H
7
3
N
4
Pyrazole
pKa: 19.8, 35.9
N1
H
7
2
4
3
2
6
3
6
Indolizine
2-Pyrroline
5
6
4
5
2
5
N
N1
H
3
2
Furan
pKa: 35.6
1
3
5
1
4
6
4
3H-Indole
7
5
N1
5
O1
4
2
N
7
2
3-Pyrroline 2H-Pyrrole
2
1
8
3
4
6
Isoindole
Carbazole
pKa: 19.9
N1
H
3
NH
7
3
2
6
8
N9
H
1
Pyrrolidine
pKa: 11.3,44
3
2
3
5
2
7
2
N1
H
4
Heterocyclic Chemistry
Essentials of Heterocyclic Chemistry-I
Baran, Richter
5
6
Morpholine
pKa: 8.4
N
H
N
S
O
Heterocyclic Aromaticity Values:
% (of PhH) β-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) β-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'
R
NH2
N
H
X
Fischer Indole Synthesis
S
N
H
NHR
R
N
H
[H]
DMAD
N+
Ph
+
R1
BrMg
R
R'
i. DMFDMA
NO2
ii. Pd/C, H2
Me
H2NNH2
R
N
H
R
ii. H+
R
Base
N
R1
R2
R2
+
R2
N
R1
R
Madelung Indole Synthesis
R
H+
CO2H
N
H
NH2
Ph
Ph
N
H
R
R
OH
i. DMAD,
piperidine
CO2Me
HS
S
CO2Me
ii. NaOMe
S
MeO2C
Fiesselmann Thiophene Synthesis
Ph
X
Ph
R1
O
S
HO2C
Hinsberg Thiophene Synthesis
CN
+
CO2H
ii. acid
O
N
R3
i. LA
Cl
OH
N
H
ii. NaBH4
X
R1
i. S8
NH2
ii. Amine
S
R2
Gewald Aminothiophene Synthesis
R2
R
N
H
Δ
X = halide
CuOTf
NH2
R
Castro Indole Synthesis
CO2R
Cl
H+
CO2R
Δ
Hemetsberger Indole Synthesis
N
H
R
Ni0
N
R
Mori-Ban Indole Synthesis
K2CO3
R
N
N
H
R
R''
CO2X
R
R'
O
R
R1
O
R2
Δ
Ph
N
OH
O
O
N
O
N
N
R
R''
O
van Leusen Oxazole Synthesis
R
R'
TosMIC
O
R'
Robinson-Gabriel Oxazole Synthesis
N
H
Bischler Indole Synthesis
CHO
R'
HCl
CN
O
R
I
R'CHO
Fisher Oxazole Synthesis
Me
N3
R1
R1
Hantzsch Pyrrole Synthesis
Me
i. NaOEt,
S(CH2CO2Et)2
O
R2
Ar
H+
Ar
H2N
Br
O
Paal Thiophene Synthesis
Sugasawa Indole Synthesis
O
X
R
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
O
CoI2, Δ
O
Graebe-Ullmann Carbazole Synthesis
R
Δ
R
HOAc
MeO2C
O
N
H
R3
O
R
O
Piloty Pyrrole Synthesis
R
R
O
N
N
Δ
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, Δ
N
H
Paal-Knorr Pyrrole Synthesis
N
R
PdII
R
Bartoli Indole Synthesis
X
O
RNH2
N
R
X
R
RNH2
R
R'
MeO
R
N
H
R1
Me
Y
O
X
Knorr Pyrrole Synthesis
Huisgen Pyrrole Synthesis
R''
R'
O
Me
R2
NH2
Ph
R2
NO2
R
CO2Me
N
Larock Indole Synthesis
Hegedus Indole Synthesis
CO2X
CO2Me
X
COY
O
O
+
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
R
NO2
R'
O
Fukuyama Indole Synthesis
NH2
Pyrroles:
N
R
i. tBuOCl
ii.Me
S
Me
AIBN
R
N
R
N
R
N
H
nBu SnH
3
X
PdII
R
R
acid, Δ
R'
R'
Pd0
Heterocyclic Chemistry
NH2OH
R'
N
O
R
Claisen Isoxazole Synthesis
O
R2
N
O
Cornforth Rearrangement
R1
HN
R
CO2H
O
N
Ac2O
R
O
O
Erlenmeyer-Plöchl Azlactone Synthesis