Functional Group Review — Comprehensive Notes
1) Alkyl groups
Alkyl groups probe the lipophilicity of a drug and contribute to overall lipophilicity (lipophilicity) of the molecule when attached to a functional group like a carboxylic acid.
Example: Valproic acid described as dipropylacetic acid.
Propyl groups contribute to lipid-like, nonpolar character.
Carboxylic acid group adds hydrophilicity (water solubility).
Alkyl groups are typically sp3 hybridized.
In drug design, alkyl groups are frequently used to probe binding sites (active sites) on targets.
Pergolide (ergoline derivative) initially used for Parkinson’s disease but caused valvular heart disease and was withdrawn in 2007.
Acts on a subset of dopamine receptors designated as D2.
The n-propyl group optimally fits a lipophilic pocket on the D2 receptor.
Extending to n-butyl decreases activity; shortening to ethyl also reduces potency because the group no longer fits the pocket well.
2) Alkyl groups (non-polar interactions)
Alkyl groups typically form non-polar interactions with non-polar regions on a drug target site (receptor) via van der Waals, hydrophobic, or induced dipole-induced dipole interactions.
Many drug receptors are proteins built from amino acids connected by peptide bonds; side chains of amino acids interact/bind with drug molecules.
3) Alkenes (C=C)
Alkenes are sp2 hybridized; have a π-cloud but are not good hydrogen bond acceptors because the π-electrons are diffuse and not readily available for H-bond formation.
Alkenes are a type of diastereoisomer with restricted rotation about the C=C bond, leading to cis/trans (Z/E) isomerism.
Pharmacological activity can be isomer-specific; example:
Chlorprothixene: only the cis-isomer is active because the dimethylamino group must be on the same side as the chloro group to access the binding site; in the trans isomer, the binding site cannot be accessed by the dimethylamino group.
4) Alkynes
Alkynes are triply bonded and have sp hybridization.
Compared to alkanes and alkenes, alkynes are more acidic, though they remain non-ionized across pH 0–14.
Rotation about the C≡C bond is restricted.
Alkynes are used for their electronic properties; their linear geometry is a hallmark.
Example: Oxybutynin (an anticholinergic agent) contains an alkyne group and is available as a hydrochloride salt due to its basic tertiary amine.
5) Ethynyl modification of estradiol (to form ethinyl estradiol)
An alkyne (ethynyl) group modifies estradiol to resist metabolism that would otherwise oxidize a secondary alcohol to a ketone; this yields estrone (more active estrogen) reduction and enables oral activity.
Ethinyl estradiol is orally active and used in combination oral contraceptives.
6) Benzyl groups
Benzyl groups are used to add lipophilicity (non-polar character).
The benzylic carbon is the methylene carbon (CH2) adjacent to the aromatic ring and is more reactive than typical alkane carbons.
Example: Ibuprofen contains a benzyl group; the benzylic carbon is identifiable adjacent to the phenyl ring.
7) N-debenzylation (benzyl groups attached to nitrogen)
Benzyl groups attached to nitrogen atoms of amines readily undergo N-debenzylation.
Example: Benzphetamine (used for weight loss) is metabolized by N-debenzylation to yield methamphetamine, contributing to its addictive potential.
8) Phenyl groups
Phenyl groups are sp2-hybridized, planar, and can bind to lipophilic areas on targets.
They interact with aromatic amino acids (phenylalanine, tyrosine, tryptophan) via π-π and hydrophobic interactions.
Example: Ibuprofen contains a benzene ring; contributes to binding via aromatic interactions.
9) Allyl groups
Allyl group: 3-carbon fragment with a double bond adjacent to a sp3 carbon.
The sp3 carbon of the allyl group is more reactive than that of an alkane due to electronic effects of the adjacent C=C bond.
Example: Naloxone contains an allyl group and antagonizes morphine at opioid receptors.
10) Alcohol groups
Alcohols (primary, secondary, tertiary) play key roles in solubility and hydrogen bonding.
Primary alcohols (RCH2OH): oxidizable to aldehydes then to carboxylic acids.
Secondary alcohols (R2CHOH): oxidizable to ketones.
Tertiary alcohols (R3COH): not easily oxidized without breaking a C–C bond.
Hydrogen bonding: alcohols can donate and accept hydrogen bonds; primary alcohols can form multiple H-bonds (two acceptors, one donor, etc.).
Example: Quetiapine contains a primary alcohol; the OH can hydrogen bond with water.
11) Phenols
Phenols are aromatic hydroxyl groups (not the same as alcohols); they are weak acids with pKa typically in the range 7–11.
Phenols can theoretically form up to three hydrogen bonds (one donor, two acceptors) due to the phenolic oxygen.
Phenolic groups increase polarity and water solubility; they also serve as handles for phase II metabolism conjugates.
Example: Morphine contains a phenolic group with pKa ≈ 9.7.
12) Ethers (ArOR and ROR)
Ethers can be aromatic or aliphatic; oxygen has two lone pairs and can act as a hydrogen bond acceptor.
Ethers add polarity to the molecule.
Example: Metoprolol contains both aliphatic and aromatic ether groups; demethylation of a methyl ether is a major metabolic pathway.
Question: Would the metabolite be more polar than the parent drug? Answer: Yes, typically, due to increased hydrogen bonding opportunities in some metabolites.
13) Aldehydes
Aldehydes (RCHO) are readily oxidized to carboxylic acids (RCOOH), making them reactive and less favorable in drugs.
Aldehydes are electron withdrawing and increase polarity.
Example: Chloral (too irritant and unstable in aldehyde form); stable as hydrate (in equilibrium with aldehyde in solution).
Aldehydes can be reduced to primary alcohols.
In some cases, aldehyde-containing drugs are converted to less reactive forms in vivo.
14) Ketones
Ketones (RRCO) are widely distributed in drugs.
They cannot be oxidized further without breaking a C–C bond but can be reduced to secondary alcohols.
Example: Tolmetin contains a ketone carbonyl that can form two hydrogen bonds (as acceptor).
Reduction product (secondary alcohol) is often more polar and sometimes more soluble.
Acetal/ketal terminology: historically, acetals were defined with aldehydes; ketals with ketones, but now “acetal” is used for products formed with any carbonyl and two alcohols.
15) Acetals (and ketals) and catechol group
Acetals/ketals formed from carbonyls with two alcohols can decrease polarity by tying up polar OH groups; this can increase lipophilicity and skin penetration in dermal formulations (cyclic acetals of diols with ketones).
Example: Triamcinolone forms a cyclic acetal with acetone; the diol portion increases polarity but the acetal ties up polar OH groups, enhancing dermal permeation.
Catechol group: 1,2-dihydroxybenzene; fun fact: two ionizable protons but only one is relevant at physiological pH; pKa ≈ 9.3.
Epinephrine contains catechol; oxidation in air yields an o-quinone.
Resorcinols: 1,3-dihydroxybenzenes; also weak acids and can form extensive H-bonds; example shows ionization in terbutaline.
16) Esters
Esters are formed from carboxylic acids and alcohols/phenols; common in drugs.
Esters can reduce polarity relative to carboxylic acids and can be hydrolyzed in vivo to liberate the active acid.
Prodrug concept: esters increase GI absorption; hydrolyzed to the active carboxylic acid in blood.
Example: Heroin is diacetylated morphine; more lipophilic and brain-penetrant; hydrolyzed to morphine by esterases.
Enalapril is an ACE inhibitor; the ethyl ester is more lipophilic and absorbed better; hydrolyzed to enalaprilat which is active.
Esters can act as hydrogen bond acceptors due to carbonyl oxygen lone pairs.
For ethyl benzoate (ethyl benzoate) question: how many H-bonds can it form? (to be discussed later).
17) Carboxylic acids
Carboxylic acids are weak acids with pKa around 4.4 in the example HA (pKa = 4.4).
Henderson-Hasselbalch: ext{pH} = ext{p}K_a + ext{log} rac{[A^-]}{[HA]}
Example: At physiological pH 7.4, 7.4 = 4.4 + ext{log} rac{[A^-]}{[HA]}
ightarrow rac{[A^-]}{[HA]} = 10^{3} = 1000:1Implications: in GI tract (pH ≈ 7 in intestine), carboxylic acids are highly ionized, increasing solubility but ionization often reduces absorption across membranes.
Carboxylic acids readily form salts with bases or with weak acids; salts generally more water soluble due to ionic interactions with water.
Amines and amide chemistry follow with ionization, salt formation, and hydrogen-bonding considerations.
18) Amines
Amines are common in drugs, especially aliphatic amines.
Amines readily form salts with acids and form hydrogen bonds.
Classification: primary, secondary, tertiary, and quaternary.
Example: Phenethylamine (a primary aliphatic amine) can form 3 hydrogen bonds (two donors and one acceptor via the nitrogen lone pair).
Amines are basic; aliphatic amines are more basic than aromatic amines due to less resonance stabilization of the lone pair.
Aromatic amines have lone pairs that can be delocalized into the ring, reducing basicity.
Example: Procainamide contains an aliphatic (more basic) amine and an aromatic (less basic) amine.
19) Hydrazines and Hydrazides
Hydrazines are basic (pKa typically 7–8 range); few drugs contain hydrazine groups.
They can form reactive metabolites and potential adverse effects.
Example: Hydralazine contains a hydrazine-like structure with resonance stabilization (guanidine-like) on the ring nitrogens; protonation occurs on ring nitrogen due to resonance.
Hydrazides (R-CONH-NH2) are weak bases; example isoniazid.
20) Benzyl hydrazide
Benzyl hydrazide is a basic fragment due to the NH2 lone pair being available for protonation.
The nitrogen adjacent to the carbonyl is less basic due to resonance with the carbonyl group.
21) Phenyl rings and halogens
Phenyl rings enhance lipophilicity; electronic properties can be altered by substituents.
Halogens (F, Cl, Br, I) are electron-withdrawing and are common on substituted phenyl rings; Cl is a classic example.
Diazepam contains a phenyl ring as part of the benzodiazepine nucleus; halogen substitution (Cl) is essential for activity.
Halogens are often para-substituents to block metabolism (para-hydroxylation). Example: Haloperidol has para-substitutions to reduce metabolism.
Task: identify ketone, tertiary heterocyclic amine, and tertiary alcohol in a given compound; identify aliphatic ether, a tertiary amine, and pyridine ring; determine hydrogen-bond counts.
22) Naphthalene rings
Naphthalene rings increase lipophilicity.
Examples: Propranolol and nabumetaone contain naphthalene rings.
23) Pyridines
Pyridine is isosteric with benzene but more polar, increasing solubility.
Like amines, pyridine acts as a hydrogen bond acceptor and can form salts with acids.
24) Lactones
Lactones are cyclic esters; properties resemble esters.
Example: Pilocarpine; hydrolyzes to pilocarpic acid (inactive).
25) Amides
Amides are formed from amines and carboxylic acids; nitrogen is resonance-delocalized, reducing basicity.
Amides are more resistant toward hydrolysis than esters due to resonance; positive charge localization differs (nitrogen vs oxygen in esters).
In vivo, amidases hydrolyze amides to carboxylic acid and amine.
Example: Atenolol (β1 antagonist) is hydrolyzed by amidases to yield an inactive carboxylic acid and ammonia; Indomethacin is a heterocyclic amide hydrolyzed to indole and carboxylic acid.
26) Lactams
Lactams are cyclic amides with hydrolysis products contained within the same molecule.
Classic example: Penicillin G (benzyl penicillin).
Complete hydrolysis products of a lactam include the corresponding amine and carboxylic acid within the same molecule.
27) Ureas
Ureas have a carbonyl flanked by two nitrogens.
Example: Sorafenib (tyrosine kinase inhibitor).
Ureas are fairly resistant to hydrolysis due to resonance stabilization.
Can act as hydrogen bond donors (if one N bears a hydrogen) and as acceptors (through carbonyl oxygen lone pairs).
Nitrogen lone pairs on ureas are generally poor H-bond acceptors due to resonance with the carbonyl.
28) Thioureas
Similar to ureas but with a thiocarbonyl (C=S) instead of C=O.
Thioureas can donate hydrogen bonds (via N–H) but are poor hydrogen-bond acceptors because sulfur lone pairs are in diffuse orbitals and less available.
The thiourea nitrogens also have resonance stabilization reducing basicity.
Some thioureas can be oxidized to reactive sulfenic acids, posing safety concerns.
29) Sulfides (thioethers), sulfoxides, and sulfones
Sulfides are thioethers (R–S–R).
Oxidation products are sulfoxides and sulfones, which are more polar and increase water solubility.
Example: Sulindac is a sulfoxide that is bioactivated to the thioether; the excreted metabolite is the sulfone.
30) Thiols (sulfhydryl groups)
Thiols ≈ mercaptans; sulfur analogs of alcohols.
Thiols are weaker acids than alcohols; typical pKa ~ 9–11.
Example: Captopril contains a thiol group; early ACE inhibitor; skin rashes and bad taste concerns due to thiol.
Thiols are prone to oxidation forming disulfides when exposed to air.
31) Carbamates
Carbamates are hybrids of esters and amides; more hydrolyzable than amides but less than esters.
Oxygen increases carbonyl electrophilicity, making carbamates more hydrolyzable than amides, but resonance with the amide-like nitrogen stabilizes the structure.
Hydrolysis products: alcohols/phenols, amines, and carbon dioxide.
Examples:
Rivastigmine: a carbamate used to treat Alzheimer's disease by inhibiting acetylcholinesterase to increase acetylcholine.
Neostigmine: another carbamate containing a quaternary ammonium; does not easily cross lipid membranes due to permanent positive charge.
Question: hydrolysis products of neostigmine?
32) Nitro groups and nitrile groups
Nitro groups: strongly electron-withdrawing; polar; aromatic nitro groups increase water solubility; reduced in vivo to amines via nitroso and hydroxylamine intermediates. Aliphatic nitro compounds are unstable and not typical in drugs.
Example: Flutamide (aromatic nitro-containing anti-androgen).
Nitrile groups: sp hybridized; non-basic; strongly electron withdrawing; increase molecular polarity.
Example: Saxagliptin contains a nitrile group.
33) Oximes and N-oxides
Oximes: formed from aldehydes/ketones with hydroxylamine; can exhibit cis/trans (E/Z) isomerism; generally weak acids (pKa > 11) and are not highly relevant at physiological pH.
N-oxides: e.g., minoxidil; well absorbed; overall neutral charge allows good membrane permeability; used in dermal preparations (e.g., Rogaine).
34) Amidines and Guanidines
Amidines: highly basic functionalities with resonance-stabilized cation; pKa ranges ~5–12.
Example: Dabigatran etexilate is a double prodrug containing an amidine that is bioactivated by esterases to dabigatran.
Guanidines: extremely basic, often protonated at physiological pH; penetration through membranes can be poor; example: argatroban (a direct thrombin inhibitor).
Argatroban is given IV because ionization would limit GI absorption.
35) Sulfonylureas
Sulfonylureas are acidic moieties with pKa around 5; important class for type 2 diabetes therapy.
Why acidic? After deprotonation on the N–H adjacent to the sulfonyl group, resonance stabilizes the resulting anion.
36) Sulfonamides
Sulfonamides are a broad class of antimicrobial agents (e.g., sulfanilamide).
Widely used in various drugs (e.g., hydrochlorothiazide, celecoxib).
Aromatic sulfonamides are more acidic than aliphatic analogs (pKa 5–11).
Reason: sulfonyl group (SO2) is strongly electron-withdrawing and stabilizes the conjugate base via resonance across O=S–O and the amide nitrogen.
37) Sulfonic acids and sulfonates
Sulfonic acids are very acidic and poorly absorbed if ionized at physiological pH; thus rarely used as free acids in drugs.
Sulfonates can be isosteres of esters; hydrolyzable, but generally more polar.
Example: Busulfan contains a sulfonate group; hydrolysis produces sulfonate derivatives and diol products.
38) Glycosides
Glycosides are sugar derivatives where the glycosidic linkage connects sugar portion to a non-sugar moiety.
Glycosides can contain C, N, S, and O linkages; linkages define the linkage chemistry and many drug conjugates rely on glycoside chemistry for prodrug strategies.
39) Imides
Imides: carbonyl flanked by two nitrogen atoms; generally weak acids with pKa ~9–11.
Examples include phenytoin, ethosuximide (imide-containing anticonvulsants) and phenobarbital (diimide).
Imides reflect resonance stabilization in their conjugate bases, contributing to acidity.
40) Imines
Imines (C=N) are sp2-hybridized and less basic than amines.
The imine functional group is found in diazepam (benzodiazepine core) as a labeled A group; the implied activity relates to the imine pathology.
41) Nitrate esters and nitrite esters
Nitrate esters: esters formed from nitric acid with an alcohol; lipophilic and vasodilatory; nitroglycerin is a classic nitrate ester used for angina.
Nitrite esters: formed from nitrous acid and an alcohol; amyl nitrite is used as a drug of abuse for CNS stimulation; amyl nitrite is derived from isoamyl alcohol.
42) Carbonates
Carbonates: general structure shown; hydrolysis yields two alcohols and CO₂.
Candesartan cilexetil is a prodrug containing a carbonate group; hydrolysis yields acetaldehyde, CO₂, and the active carboxylic acid cilexetil.
Complete hydrolysis of a carbonate yields two alcohols plus CO₂.
43) Anhydrides
Anhydrides formed by dehydration of two carboxylic acid equivalents; readily hydrolyzed to carboxylic acids, thus limited therapeutic use.
BCNU example: anhydride linkages in polymeric film deliver drug to tumor resection site; hydrolysis releases active agent.
44) Hydrazones
Hydrazones: formed from ketones/aldehydes with hydrazines; hydrolyze back to ketones and hydrazines.
45) Quick Q&A review (selected questions and answers from the reading)
Q: How many hydrogen bonds can the secondary alcohol group of propranolol form? A: 3
Q: If morphine is placed in a NaOH solution at pH 11.7, would morphine be predominantly positively charged, neutral, or negatively charged? A: Negatively charged
Q: Demethylation of a methyl ether (as in metoprolol) increases polarity; would the metabolite be more polar? A: Yes, more polar
Q: Between tolmetin and its secondary alcohol metabolite, which is more water soluble? A: The secondary alcohol metabolite is more water soluble due to increased hydrogen bonding capacity (3 H-bonds vs 2 for the ketone)
Q: How many H-bonds can a catechol group form? A: 6
Q: Resorcinols can form extensive H-bonds. Give the maximum number of H-bonds for resorcinol. (Answer aligned with catechol-like expectations in the notes.)
Q: Hydrolysis of an ester always yields an alcohol/phenol and a carboxylic acid. (Answer: true)
Q: In theory, how many hydrogen bonds can ethyl benzoate form? (Answer: 2)
Q: Identify a ketone, a tertiary heterocyclic amine, and a tertiary alcohol in a given compound. (Answer: depends on the structure; students should inspect the structure for the labeled A, B, etc.)
Q: Identify the aliphatic ether, the tertiary amine, and the pyridine ring in a given compound; how many H-bonds can be formed? (Answer: 4 H-bond acceptors in one example; see the solution key for details.)
Q: Complete hydrolysis products of penicillin? (Answer: penicillin yields amine and carboxylic acid fragments after beta-lactam hydrolysis.)
46) Argatroban (IV-only) and related acidic/basic groups
Argatroban contains both an acidic carboxylic acid group and a strongly basic guanidinium group.
Its zwitterionic nature at physiological pH reduces GI absorption, which is why it is given IV.
47) Summary of key concepts and practical implications
Ionization state (pKa, pH) strongly influences solubility and absorption; Henderson-Hasselbalch relations guide predictions in GI tract vs blood.
Lipophilicity vs polarity balance governs membrane permeability and distribution.
Hydrogen bonding capacity of functional groups influences solubility, binding interactions, and metabolism.
Prodrug strategies often use esters, carbonates, or phosphate/sulfate groups to improve bioavailability; in vivo hydrolysis yields active drug.
Metabolic considerations (oxidation, reduction, hydrolysis) differ across functional groups (e.g., oxidation of alcohols to aldehydes/ketones, dealkylation, N-debenzylation).
Pharmacokinetic implications of functional groups (e.g., sulfonamides as acids, guanidines as highly basic and poorly membrane-permeable).
48) Practice prompts and final reminders
Be able to classify compounds by functional group, predict hydrogen bonding capacity, count potential H-bonds, and infer solubility/absorption implications.
Be able to explain why certain functional groups increase or decrease pharmacokinetic properties (lipophilicity, polarity, H-bonding, ionization).
Review specific drug examples mentioned (e.g., Valproic acid, pergolide, ibuprofen, propranolol, quetiapine, enalapril, rivastigmine, penicillin G, diazepam, haloperidol, doxylamine, doxylamine, etc.) to connect theory with real-world drugs.
49) Quick reference list of key terms
Alkyne, Alkenes, Alkyl, Benzyl, Benzylic
Phenyl, Naphthalene, Pyridine
Allyl, Alcohols (primary/secondary/tertiary), Phenols
Ethers, Aldehydes, Ketones, Esters, Acetals/ketals
Catechol, Resorcinol, Amides, Ureas, Imides, Imines
Nitrile/Nitro, Oximes, N-oxides, Amidines, Guanidines
Sulfonylureas, Sulfonamides, Sulfonates, Sulfonic acids
Glycosides, Lactones, Anhydrides, Carbonates, Phosphate esters
Hydrazines/Hydrazides, Thiols, Sulfides/Sulfoxides/Sulfones
Nucleophilicity, Electronegativity, Resonance stabilization, pKa, Henderson-Hasselbalch
Note: If you’d like, I can convert this into a printable study sheet with a compact index and quick icons for each functional group.
There are 38 functional groups listed and described: Acetals/Ketals, Alcohols, Aldehydes, Alkenes, Alkyl, Alkyne, Allyl, Amides, Amidines, Anhydrides, Benzyl, Carbamates, Carbonates, Catechol, Esters, Ethers, Glycosides, Guanidines, Hydrazides, Hydrazines, Hydrazones, Imides, Imines, Ketones, Lactones, Naphthalene, Nitrile, Nitro, N-oxides, Oximes, Phenols, Phenyl, Phosphate esters, Pyridine, Resorcinol, Sulfides (Thioethers), Sulfonamides, Sulfonates, Sulfones, Sulfonic acids, Sulfoxides, Sulfonyl
Here are the 38 functional groups in alphabetical order:
Acetals/Ketals
Alcohols (primary/secondary/tertiary)
Aldehydes
Alkenes
Alkyl
Alkyne
Allyl
Amides
Amidines
Anhydrides
Benzyl
Carbamates
Carbonates
Catechol
Esters
Ethers
Glycosides
Guanidines
Hydrazides
Hydrazines
Hydrazones
Imides
Imines
Ketones
Lactones
Naphthalene
Nitrile (Cyano)
Nitro
N-oxides
Oximes
Phenols
Phenyl
Phosphate esters
Pyridine
Resorcinol
Sulfides (Thioethers)
Sulfonamides
Sulfonates
Sulfones
Sulfonic acids
Sulfoxides
Sulfonylureas
Thiol (Sulfhydryl)
Ureas