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Transcript
FUNCTIONAL GROUP
REVIEW
Pharm 312
Lect 2
& Lab-1&2
1
FUNCTIONAL GROUP REVIEW
• Introduction:
Drugs are organic compounds,
Interaction of a drug with a receptor or enzyme
depends on characteristics of drug molecule.
• Exs. Aspirin or
• Acetyl salicylic acid
• Pencillin
2
Some Types of Functional Groups
Class
Gen-Formula Functional group Specific example
Haloalkane (R-X)
-X (-F, -Cl, -Br)
CH3Cl
Alcohol
(R-OH)
-OH
CH3OH
Ether
(R-O-R)
-O-
CH3-O-CH3
O
O
Aldehyde (RCHO)
C
Ketone
O
O
C
CH3CCH3
(RCO)
H
CH 3 CH
3
MORE FUNCTIONAL GROUPS
Class
Gen-Formula Functional group
Carboxylic acid
-COOH
Specific example
CH3COOH
(RCOOH)
Ester
(RCOOR)
-COO-
CH3COOCH3
Amine
(RNH2)
-NH2
CH3NH2
-CONH2
CH3CONH2
Amide
(RCONH2)
4
Class
General formula
O
R C OH
Carboxylic acid
Ester
Acid chloride
Acid anhydride
O
R C O R
O
R
C Cl
O
O
R C O C R
Functional group
O
C OH
O
C O R
Specific example
CH3
O
H3C C O CH3
O
C Cl
O
O
C O C
O
C OH
O
H3C
C Cl
O
H3C
C O
O
C CH3
In these classes of compounds R may be H or alkyl group R=CH3,C2H5,etc
5
FUNCTIONAL GROUP REVIEW
• Carbon with 3 distinct geometric forms:
• Sp3 – Alkanes ex- Methane (CH4)
• Sp2 - Alkenes
ex- Ethene (C2H4)
• sp – Alkynes
ex- Ethyne (C2H2)
6
STRUCTURE OF METHANE (CH4)
• Shape= Tetrahedral
• Bond angle H-C-H = 109.280 (109.50)
• Chirality found: Carbon attached with 4different groups.
H
Bond length 1.09 A0
H
C
109.280 Bond angle
H
H
Bond energy 101 Kcal/mole
7
FORMATION OF METHANE MOLECULE
• sp3 Hybridization
• Atomic configuration of C:
• Atomic mass = 12
• Atomic number= 6 ( 1s2, 2s2,2px1,2py1,2pz0 )
2 p1x 2 p 1y 2p
z
1
2 p1x 2 p y 2 p1
z
promotion
Energy
Sp 3
hybridization
orbital
2S1
2S2
1S2
1S2
1S2
(a)
(b)
(c)
8
DIAGRAM SHOWS THE FORMATION OF CH4
MOLECULE.
• 4s orbital of H + 4sp3 orbital of C atom = Methane
molecule
109.47 0
109.47 0
C
109.47 0
109.47 0
H
H CH
H
• Properties: Alkanes are water insoluble, as have
no electronegative groups or dipolemonent.
• Are chemically unreactive
9
ISOMERISM
• Compounds with single chiral center exist as
enentiomers (mirror images). See below
10
FORMATION OF C=C DOUBLE BOND IN ETHENE
Ethene
Shape: planar- trigonal
C=C Bond Length: 1.34 A0
Bond Angle: 1200
120
1.34A
SP2
SP2
2
SP2 SP
sp2
Hybridization:
H
SP2
C
C
SP2
H
Atomic configuration126of C
2p
Atomic mass = 12
Atomic number= 6 (1s2, 2s2, 2px1, 2py1, 2pz0 )
11
sp2 HYBRIDIZATION
2 p1x 2 p 1 2 p
y
z
2 p1x 2 p 1y 2 p1z
promotion
Energy
1
2p z
hybridization
2 S2
Sp2 orbital
2S1
1S2
1S2
(a)
1S2
(b)
Double bond is formed by the overlap
of two sp2 orbital one from each
carbon to make  sigma bond and
then the overlap of pz orbital from
each carbon to form  bond.
12
STRUCTURE OF ALKENES
Alkenes have three sp2 hybridized orbital and one
p orbital, and have bond angles of about 120
degrees.
1200
C
C
C .. C
P
H
H
Kekule Structure
Lewis Structure
sp2
sp2
C
P
sp2
sp2
C
sp2
sp2
H
H
Orbital Representation
Properties: Alkenes are low water soluble, as
have no dipolemoment & no H-bonding with
water molecules.
Are chemically unreactive.
13
STRUCTURE OF ETHYNE
• Alkynes have two sp hybridized orbital and two
2p orbital, and have bond angles of 180 degrees.
180
0
1.20A
14
STRUCTURE OF ETHYNE
Px
Px
Py
Py
SP
SP
SP
SP
HC CH
Py
Kekule Structure
Px
Py
Px
Orbital Representation
CH CH
Lewis Dot Structure
15
HETEROATOMS IN DRUG MOLECULES
• Nitrogen: Lone pair at N¨ determines the acidbase properties of drug molecule at
physiological pH.
• Walden (rapid) inversion: Lone pair shifts from
one side of atom to other & back again.
• Oxygen:
16
HETEROATOMS IN DRUG MOLECULES
• Phosphorous: In drug molecules P as trivalent
(with lone electron pair), Pentavalent (without
lone pair of electron).
• Sulphur:
17
GEOMETRIC ISOMERS OF ALKENES
• cis and trans forms
OR (from German)
• Z-isomer (zusammen i.e together) &
• E-isomer (entgegen i.e opposite)
H
H
C
H3C
H
CH3
C
C
CH3
Z-form or cis-2-butene
H3C
C
H
E-form or trans-2-butene
18
AROMATIC HYDROCARBONS
O. Benzene (C6H6) is a planar, cyclic and
conjugated system.
O. Each carbon in benzene is sp2 hybridize
& attached to three other atoms (2-C &
1-H atom)
O. Bond angles in benzene are 1200.
O. all carbon-carbon bonds length are
equal & =1.39A. (Evidence revealed from x-ray
diffraction experiments)
O. The typical reaction of benzene is
substitution, rather than addition.
19
AROMATIC HYDROCARBONS
The true structure of benzene can be
explained by the concept of resonance.
Benzene is a resonance hybrid (III) of
two imaginary contributing structures ( I
and II )
Equivale nt to
(II)
(I)
ContributingStructure
(III)
Re s onance hybrid
20
AROMATIC CHARACTER
The (4n +2) π Rule
1. All aromatic compounds are cyclic and
fully conjugated.
2. Atoms in the ring are sp2 hybridized.
3. They Obey Huckle's rule- Aromatic
compounds contain ((4n +2) π
electrons (where n=1,2,3,4,5…).
4. According to Huckel - compounds
having 2,6 10,14,18,22… π-electrons
should be aromatic.
21
System containing: 6 π electrons
N
..
Benzene
Pyridine
..
..
O
..
Pyrrole
Furan
NH
..
S
..
Thiophene
10 π electrons
..
NH
..N
Naphthalene
Quinoline
Indole
10 π electrons
Anthracene
22
Phenanthrene
MONO SUBSTITUTED BENZENE
DERIVATIVES
Cl
Br
F
I
Br
Bromobenzene
Chlorobenzene
Fluorobenzene Iodobenzene
Derivatives have strong dipole moment due to E.N-halogens, But
unable to H-bond so poor water solubility.
Water solubility of Organic compounds depends on:
1) Formation of H-bond with water
2) Its dissociation to form an ion.
23
FUNCTIONAL GROUP REVIEW
• Hydrocarbons bonded to Heteroatoms:
• Drug molecules can H-bond & show some degree
of water solubility due to atoms like O, N, & S.
• Alcohols: Compounds with -OH hydroxyl
group. Ex. CH3-OH, CH3CH2-OH, C6H5-OH
OH
Phenols
24
COMPOUNDS WITH OXYGEN ATOMSP-358
Alcohols -OH hydroxyl
CH3-OH
CH3CH2-OH
OH
OH
Phenols
Ethers
-O-
CH3-O-CH3
25
CLASSIFICATION OF ALCOHOLS
C
OH
Carbinol group
Examples
R
C
OH
H
Primary alcohol
10 ROH
OH
R
H
H
R
C
OH
R
Secondary alcohol
2 0 ROH
H2 C
OH
R
C
OH
R
Tertiary alcohol
30ROH
CH 3
OH
26
SECONDARY ALCOHOLS
OH
R
Alcohol
CH R
Common name
IUPAC name
Isopropyl alcohol
(2-Propanol)
OH
CH3CHCH 3
Tertiary Alcohol
OH
H3C
C
CH3
t -Butyl alcohol
(2-Methyl-2-Propanol)
CH3
27
PHYSICAL PROPERTIES OF ALCOHOLS
Solubility: Alcohols possess Permanent dipole & make Hbond.
R
O
R
R
H.....O
H.....O
H
Drugs with alcohol groups can Hydrogen bond and soluble
in water. Lowest alcohols are completely miscible in water.
O
δ-
H
O ------- H
R
δ+
δ-
O ------ H
H
δ+
δ-
O
R
H
O
.H
H.
... ...
..
O
H.
H3 C
...
.
H
O
H
H
28
BIOLOGICAL OXIDATION OF ALCOHOLS
• Biological Oxidation is an important feature in
metabolism & excretion of many drugs.
Oxidation of tert-alcohol does not occur.
29
BIOLOGICAL OXIDATION OF ALCOHOLS
Oxidation of Primary Alcohol
Examples
OH
1. H3C
C
O
O
H
Oxidizng agent
H
ethanol
C
H
ethanal
OH
2.
H3C
C
H
benzyl alcohol
O
H
Oxidizng agent
O
C
H
benzadehyde
30
OXIDATION OF SECONDARY ALCOHOL
O
O
H
O
R
Example
C
R
R
C
R
+
H2O
H
O
OH
O
H3C
C
H3C
CH3
H
C
CH3 + H2O
Propanone
2-Propanol
Tertiary Alcohols Resist oxidation
No double
O
bond
forms
R
C
30
H
R
No hydrogen on
this carbon
O
No -Oxidation product
R
Alcohols
31
PHENOL-BENZENE WITH A HYDROXYL
GROUP
 Phenols in Medicine
OH
OH
OH
OH
OH
CH2CH2CH2CH2CH2CH3
Phenol
Resorcinol
(antiseptic)
4-Hexylresorcinal
(antiseptic)
32
PHENOLS - PROPERTIES
• Phenols are weak acids: they dissociate in
water to form phenolate anion.
• Phenol acidity is strongly affected by other
substituents on ring, for example,
• p-nitrophenol is > acidic then phenol due
to EWG nitro and p-ethylphenol is less
acidic due to ERG ethyl.
• When phenolic drugs needed to dissolve in
aq-environment then they are treated with
aq-bases to form salt. See next slide
33
PHENOLS - PROPERTIES
34
ETHERS & PROPERTIES
• Contain an -O- between two carbon groups
CH3-O-CH3
dimethyl ether
CH3-O-CH2CH3 ethyl methyl ether
Can H-bond weakly with water, but not so
polar to be water soluble.
Chemically inert unless exposed to spark
or flame.
35
ETHERS AS ANESTHETICS
 Anesthetics inhibit pain signals to the brain
 CH3CH2-O-CH2CH3 used for over a century
(Morton, 1846)
 Causes nausea and is highly flammable
 1960s developed nonflammable anesthetics
Cl F F
Cl F H
H-C-C-O-C-H
F F
F
Ethane(enflurane)
H-C-C-O-C-H
HF
H
Penthrane
36
ALDEHYDES AND KETONES
O
C
Carbonyl group
Ketone
Aldehyde
O
O
C
C
R
H
RCHO
O
H3C C H
Acetaldehyde
R
R
RCOR
O
H3C C CH3
Acetone
37
Aldehydes and Ketones
 In an aldehyde, an H atom is attached to a
carbonyl group
O
carbonyl group

CH3-C-H
 In a ketone, two carbon groups are attached to
a carbonyl group
O

CH3-C-CH3
carbonyl group
38
Naming Aldehydes
 IUPAC Replace the -e in the alkane name -al
 Common Add aldehyde to the prefixes form (1C),
acet (2C), propion(3), and butry(4C)
O
O
O



H-C-H
CH3-C-H
CH3CH2C-H
methanal
ethanal
propanal
(formaldehyde) (acetaldehyde) (propionaldehyde)
O CH3
H3C
C
CH CH3
3-Methyl-2-butanone
39
PROPERTIES
Electro –ve O pulls electrons & sets up dipole
moment. So δ+ on sp2 carbonyl-C & δ- on O.
Aldehydes & ketones can form H-bond, H2O
soluble.
Show Keto-enol tautomerism
Nucleophilic Substitution: Carbonyl carbon
due to δ+ exposed to nucleophilic attack. See
next slide
40
PROPERTIES OF ALDEHYDES & KETONES
41
AMINES-ORGANIC COMPOUNDS OF
NITROGEN
• The most prevalent acid-base functional
group in drug molecules.
• Classified as primary, secondary, tertiary
CH3
CH3


CH3—NH2 CH3—NH CH3—N — CH3
1°
2°
3°
42
Classification of Amines
Ammonia
..
H
N
H
H
Primary Amine
R
Examples
CH3
..
N
H
Secondary Amine
R
..
N
R
Tertiary Amine
R
..
N
H
H
R
..
..
..
N
H
H
CH3
N
H
CH3
CH3
N
R
CH3
CH3
43
AMINES-ORGANIC COMPOUNDS OF
NITROGEN
• Pri, sec, tert-amines due to lone pair
behave weak bases.
• Quaternary ammonium due to +ve charge is
neutral.
• Form H-bond so water soluble.
• Amines form salts due to available lone
pair. See next slide
44
AMINES-ORGANIC COMPOUNDS OF
NITROGEN
• Structure & Properties:
•Amides show tautomerization & neutral
45
ALKALOID DRUG
MORPHINE
• Functional Groups in Morphine: tert-amine
& phenolic hydroxyl have acid-base
characteristics in vivo.
• With HCl form salt of the acid-soluble in
water.
• With NaOH form Na-phenolate salt –
water soluble. See next slide
46
ALKALOID DRUG-MORPHINE
47
CARBOXYL GROUP
Carboxylic acids contain the carboxyl group on
carbon 1.
O

CH3 — C—OH
=
CH3—COOH
carboxyl group
Structure
O
Hybridization= sp2
bond angles = 1200
OH
Configuration = planar
carbonyl group
C
hydroxyl group
carboxyl group
48
PROPERTIES OF CARBOXYLIC ACID
Carboxylic acids
49
PROPERTIES OF CARBOXYLIC ACID
Carboxylic acids are polar compound and
may exist as dimers.
O
R
O
.....H
O
Two polar groups
C
R
O
H
C
C
O
H
R
..... O
EWG (Electron withdrawing group)-added to ∞-C, acidity is
enhanced. Fluoromethyl acetic acid > acidic then
acetic acid.
50
SOLUBILITY
Carboxylic acids with one to four carbons are very soluble in water,
because of H---bonding with water molecules.
O
O
H. . .
H
........
O
C
H3C
H
....
.H
H
H
H
. ...
.O
.
H
O
..
..
H
. . . .O
H
Hydrogen bond
H
O
Acidity of Carboxylic Acids
Carboxylic acids are weak acids as they ionize in water to give acidic
solution.
O
R
C
O
OH
+ H2O
+ H3O
R
C O
Carboxlate ion Hydronium ion
Carboxylic acids are better acids than phenols and alcohols.
Acidity:
RCOOH > ArOH > ROH
51
PROPERTIES
(ACIDITY OF CARBOXYLIC ACIDS)
• Carboxylic acids are weak acids
CH3COOH + H2O
H3O+
CH3COO– +
• Neutralized by a base
CH3COOH + NaOH
+H2O
CH3COO– Na+
52
DERIVATIVES OF CARBOXYL GROUP
FOUND IN DRUGS
53
DERIVATIVES OF CARBOXYL GROUP
FOUND IN DRUGS
• Lactones and Lactams
54