2 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
3 Some Types of Functional Groups Class Gen-Formula Functional group Specific example Haloalkane (R-X) -X (-F, -Cl, -Br) CH 3 Cl Alcohol(R-OH) -OHCH 3 OH Ether(R-O-R) -O-CH 3 -O-CH 3 Aldehyde (RCHO) Ketone (RCO)
4 MORE FUNCTIONAL GROUPS Class Gen-Formula Functional group Specific example Carboxylic acid -COOH CH 3 COOH (RCOOH) Ester (RCOOR) -COO- CH 3 COOCH 3 Amine (RNH2) -NH 2 CH 3 NH 2 Amide (RCONH2) -CONH 2 CH 3 CONH 2
5 Class General formula Functional group Specific example Carboxylic acid Ester Acid chloride Acid anhydride In these classes of compounds R may be H or alkyl group R=CH 3,C 2 H 5,etc
7 STRUCTURE OF METHANE (CH 4 ) Shape= Tetrahedral Bond angle H-C-H = 109.28 0 (109.5 0 ) Chirality found: Carbon attached with 4- different groups. 109.28 0 1.09 A 0 Bond length Bond angle 101 Kcal/mole Bond energy HH H H C
8 FORMATION OF METHANE MOLECULE sp 3 Hybridization Atomic configuration of C: Atomic mass = 12 Atomic number= 6 ( 1s 2, 2s 2,2px 1,2py 1,2pz 0 )
9 DIAGRAM SHOWS THE FORMATION OF CH 4 MOLECULE. 4s orbital of H + 4sp3 orbital of C atom = Methane molecule Properties: Alkanes are water insoluble, as have no electronegative groups or dipolemonent. Are chemically unreactive
10 ISOMERISM Compounds with single chiral center exist as enentiomers (mirror images). See below
11 FORMATION OF C=C DOUBLE BOND IN ETHENE Ethene Shape: planar- trigonal C=C Bond Length: 1.34 A 0 Bond Angle: 120 0 sp 2 Hybridization: Atomic configuration of C Atomic mass = 12 Atomic number= 6 (1s 2, 2s 2, 2px 1, 2py 1, 2pz 0 )
12 sp2 HYBRIDIZATION 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.
13 STRUCTURE OF ALKENES Alkenes have three sp2 hybridized orbital and one p orbital, and have bond angles of about 120 degrees. Kekule StructureLewis StructureOrbital Representation Properties: Alkenes are low water soluble, as have no dipolemoment & no H-bonding with water molecules. Are chemically unreactive.
14 STRUCTURE OF ETHYNE Alkynes have two sp hybridized orbital and two 2p orbital, and have bond angles of 180 degrees.
15 STRUCTURE OF ETHYNE Kekule Structure Lewis Dot Structure Orbital Representation
16 HETEROATOMS IN DRUG MOLECULES Nitrogen: Lone pair at N¨ determines the acid- base properties of drug molecule at physiological pH. Walden (rapid) inversion: Lone pair shifts from one side of atom to other & back again. Oxygen:
17 HETEROATOMS IN DRUG MOLECULES Phosphorous: In drug molecules P as trivalent (with lone electron pair), Pentavalent (without lone pair of electron). Sulphur:
18 GEOMETRIC ISOMERS OF ALKENES cis and trans forms OR (from German) Z-isomer (zusammen i.e together) & E-isomer (entgegen i.e opposite) Z-form or cis-2-butene E-form or trans-2-butene
19 AROMATIC HYDROCARBONS O. Benzene (C 6 H 6 ) 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 120 0. 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.
20 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 )
21 AROMATIC CHARACTER The (4n +2) π Rule 1.All aromatic compounds are cyclic and fully conjugated. 2.Atoms in the ring are s p 2 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.
22 System containing: 6 π electrons 10 π electrons
23 MONO SUBSTITUTED BENZENE DERIVATIVES 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.
24 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. CH 3 -OH, CH 3 CH 2 -OH, C6H5-OH Phenols
27 SECONDARY ALCOHOLS AlcoholCommon nameIUPAC name Tertiary Alcohol
28 PHYSICAL PROPERTIES OF ALCOHOLS Solubility: Alcohols possess Permanent dipole & make H- bond. Drugs with alcohol groups can Hydrogen bond and soluble in water. Lowest alcohols are completely miscible in water. δ- δ+ δ- δ+ δ-
29 BIOLOGICAL OXIDATION OF ALCOHOLS Biological Oxidation is an important feature in metabolism & excretion of many drugs. Oxidation of tert-alcohol does not occur.
30 Examples Oxidation of Primary Alcohol BIOLOGICAL OXIDATION OF ALCOHOLS
31 OXIDATION OF SECONDARY ALCOHOL Example Tertiary Alcohols Resist oxidation
32 PHENOL-BENZENE WITH A HYDROXYL GROUP Phenols in Medicine
33 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
35 ETHERS & PROPERTIES Contain an -O- between two carbon groups CH 3 -O-CH 3 dimethyl ether CH 3 -O-CH 2 CH 3 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.
36 ETHERS AS ANESTHETICS Anesthetics inhibit pain signals to the brain CH 3 CH 2 -O-CH 2 CH 3 used for over a century (Morton, 1846) Causes nausea and is highly flammable 1960s developed nonflammable anesthetics Cl F F Cl F HH-C-C-O-C-H F F F H F H Ethane(enflurane) Penthrane
38 Aldehydes and Ketones In an aldehyde, an H atom is attached to a carbonyl group Ocarbonyl group CH 3 -C-H In a ketone, two carbon groups are attached to a carbonyl group Ocarbonyl group CH 3 -C-CH 3
39 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 CH 3 -C-HCH 3 CH 2 C-H methanal ethanal propanal (form aldehyde) (acetaldehyde) (propionaldehyde) 3-Methyl-2-butanone
40 PROPERTIES Electro –ve O pulls electrons & sets up dipole moment. So δ+ on sp 2 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
44 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
45 AMINES-ORGANIC COMPOUNDS OF NITROGEN Structure & Properties: Amides show tautomerization & neutral
46 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
48 CARBOXYL GROUP Carboxylic acids contain the carboxyl group on carbon 1. O CH 3 — C—OH= CH 3 —COOH carboxyl group Structure Hybridization= sp2 bond angles = 120 0 Configuration = planar
49 PROPERTIES OF CARBOXYLIC ACID Carboxylic acids
50 PROPERTIES OF CARBOXYLIC ACID Carboxylic acids are polar compound and may exist as dimers. EWG (Electron withdrawing group) -added to ∞-C, acidity is enhanced. Fluoromethyl acetic acid > acidic then acetic acid.
51 SOLUBILITY Carboxylic acids with one to four carbons are very soluble in water, because of H---bonding with water molecules. Acidity of Carboxylic Acids Carboxylic acids are weak acids as they ionize in water to give acidic solution. Carboxylic acids are better acids than phenols and alcohols. Acidity: RCOOH > ArOH > ROH
52 PROPERTIES (ACIDITY OF CARBOXYLIC ACIDS) Carboxylic acids are weak acids CH 3 COOH + H 2 O CH 3 COO – + H 3 O + Neutralized by a base CH 3 COOH + NaOH CH 3 COO – Na + +H 2 O
53 DERIVATIVES OF CARBOXYL GROUP FOUND IN DRUGS
54 DERIVATIVES OF CARBOXYL GROUP FOUND IN DRUGS Lactones and Lactams