Transcript 2-new review of functional groups

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)
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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
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FUNCTIONAL GROUP REVIEW
• Carbon with 3 distinct geometric forms:
• Sp3 – Alkanes ex- Methane (CH4)
• Sp2 - Alkenes
ex- Ethene (C2H4)
• sp – Alkynes
ex- Ethyne (C2H2)
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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
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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)
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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
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ISOMERISM
• Compounds with single chiral center exist as
enentiomers (mirror images). See below
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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 )
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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.
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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.
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STRUCTURE OF ETHYNE
• Alkynes have two sp hybridized orbital and two
2p orbital, and have bond angles of 180 degrees.
180
0
1.20A
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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
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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:
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HETEROATOMS IN DRUG MOLECULES
• Phosphorous: In drug molecules P as trivalent
(with lone electron pair), Pentavalent (without
lone pair of electron).
• Sulphur:
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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
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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.
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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
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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.
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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
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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.
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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
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COMPOUNDS WITH OXYGEN ATOMSP-358
Alcohols -OH hydroxyl
CH3-OH
CH3CH2-OH
OH
OH
Phenols
Ethers
-O-
CH3-O-CH3
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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
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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
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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
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BIOLOGICAL OXIDATION OF ALCOHOLS
• Biological Oxidation is an important feature in
metabolism & excretion of many drugs.
Oxidation of tert-alcohol does not occur.
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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
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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
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PHENOL-BENZENE WITH A HYDROXYL
GROUP
 Phenols in Medicine
OH
OH
OH
OH
OH
CH2CH2CH2CH2CH2CH3
Phenol
Resorcinol
(antiseptic)
4-Hexylresorcinal
(antiseptic)
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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
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PHENOLS - PROPERTIES
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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.
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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
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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
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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
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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
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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