Functional Groups in Drug Action Sanchez, L. (2016). Functional Groups in Drug Action. Lecture presented at PHAR 422 Lecture in UIC

College of Pharmacy, Chicago. Introduction to Functional Groups

Amine - e- donating when adjacent to pi

system

Amide – has resonance

Carbamate – has resonance

Carbonate – has resonance

Urea - has resonance Amidine - has resonance

Guanidine – very basic, has resonance

Thioether – very reactive

Sulfoxide – very polar, has resonance

Sulfonamide – not very reactive

Phosphate – weak acid, good buffer

Phosphonate – weak acid, soluble

Alkyl – e- donating Aryl – if sub. is electrophilic, will have resonance

Aromatic – highly stable pi system.

hydrophobic

Alcohol/hydroxyl - e- w/drawing

Phenol – has resonance

Ether – reactive but neutral

Aldehyde – very reactive

Ketone

Acetal – stable, slightly basic

Ketal – stable, slightly basic

Carboxylic acid – acidic, has resonance

Ester – slightly basic, has resonance

*More red more basic *More blue = more acidic

Valence: The number of bonds an atom likes to make. Easy to think of it as the number of

hydrogens that can be attached to an atom to make it neutral. If the atom makes more bonds

than their valence, they will have a net positive charge. If the atom makes less bonds than their

valence, they will have a net negative charge.

o Carbon – 4 bonds

o Nitrogen – 3 bonds

o Phosphorus – 5 bonds

▪ Hydrophobic – poor solubility in water

o Mostly protons and carbons

• Hydrophilic – good solubility in water

o Usually hydrogen bond, ionize, and are charged

• Know what makes a drug more hydrophobic/hydrophilic

o Aromatics increase the hydrophobicity

o Halogen substituents increase the hydrophobicity

Ibuprofen Flurbiprofen

• Functional groups give the drug it’s properties/activity

• Electronegativity increases going from the bottom left of the periodic table to the top right

o More electronegative, less likely to make multiple bonds

• Resonance – movement/distribution of electrons

o Electrons can distribute through aromatic rings, double bonds, triple bonds, oxygen,

sulfur, phosphorous, and nitrogen

o Resonance makes something more stable and less reactive

• Induction – permanent state of polarization between two atoms

o Electron density in a sigma bond is not uniform. The more electronegative atom retains

more of the electron density

• Electron donating – Nucleophilic (electron rich).

Example: Ibuprofen vs Flurbiprofen. Flurbiprofen more hydrophobic because 2 aromatic rings and halogen

substituent (F).

Example of different bonds:

Ionic bond – chlorine so much more electronegative than sodium that it retains the negative charge (does

not want to share the electron)

Polar covalent bond – Chlorine slightly more electronegative than carbon, so retains a partial negative

charge and shares the electron a bit with the carbon

Non-polar covalent bond – Same electronegativity between both hydrogens, so equal sharing of electrons

(net neutral charge)

o More electron donating groups, more basic the molecule is

• Electron withdrawing – electrophiles (electron poor)

o More electron withdrawing groups, more acidic the molecule is

• Sterics – the bulkiness of a molecule

o Effects metabolism, reactivity, target bindin

Example: Resonance vs Induction

Resonance refers to all the structures that represent a molecule. One Lewis structure cannot

completely define the molecule.

Hints for where resonance occurs: pi donors. The electrons have to have somewhere to go

- Amide group

- Amine

- Hydroxyl

- -OR

Hints for where induction occurs: sigma donors

- R (alkyl groups)

- Aryl groups

Amino Acids

• Amino acids – building blocks of life. Amine bonds tie them together

o Glycine is smallest, most flexible, no sterics

o Ala, Val, Leu, Ile are aliphatic hydrocarbons. No resonance

o Proline is not flexible, sterically hindered, lipophilic

o Phe, Trp, Tyr are aromatics. Bulky, sterically hindered. Planar b/c of double bonds.

Lipophilic

o Tyr, Ser, Thr are nucleophiles. Have inductive effect and are hydrophilic. Can be

deprotonated in an active site

o Cys, Met are sulfur containing amino acids. Sulfur can make 2, 4, or 6 bonds. Very

reactive and more organic than hydrophilic

o Asp, Glu are acidic amino acids. Can resonate, are hydrophilic, H-bond acceptors, kind of

bulky

o Asn, Gln are amide containing amino acids. Water soluble, bulky, can resonate but not

super reactive

o Lys, Arg, His are basic amino acids. Are soluble, want to accept protons. Lys has

inductive effects, Arg and His can resonate

• Electronics, Sterics, and Solubility are chemical properties

• Resonance and Induction are electronic effects

Acids vs. Bases

▪ Phenols are weak acids and metabolized in the body

▪ Carboxylic acids are acids

o Usually charged at body pH (carboxylate)

▪ The more acidic the environment, the more likely a functional group will want to accept

a proton

o Ex) Carboxylic acids will accept H+ in the acidic stomach, becoming neutral

▪ Imides and dicarbonyls can steal H+ from carbon and nitrogen because resonance

stabilizes the structures

▪ Sulfonamides and sulfonylureas undergo resonance. Sulfur can make 2, 4, or 6 bonds

o Sulfonamides become more acidic next to an electron w/drawing group

o Sulfonylureas are more acidic because there is more resonance and can

delocalize electrons

▪ Sulfates, phosphates, and phosphonates will be ionized at body pH because they’re very

acidic (they lose a hydrogen, accept electrons)

o Addition of one of these functional groups increases solubility of the drug

▪ Aliphatic amines are weak bases

▪ Aromatic amines are weak acids b/c of resonance

▪ Imines are weak acids b/c of conjugation

▪ Amidines are more basic because of resonance

▪ Guanidine is very basic because of even more resonance

*When something is acidic, it is more likely to donate a hydrogen and accept electrons.

▪ - If the molecule can use resonance, this will increase the acidity because the extra

electrons can be delocalized

▪ - Again… RESONANCE INCREASES STABILITY OF A CHARGE

* When something is basic, it is more likely to accept a hydrogen and donate electrons.

▪ - Resonance can increase basicity within a functional group (ex. Guanidine) but

resonance will decrease basicity if the functional group is attached to an electron

withdrawing group (like an aromatic ring)

▪ Electron withdrawing groups increase acidity and decrease basicity

▪ Electron donating groups decrease acidity and increase basicity

Solubility

▪ An amphoteric molecule can be either positively charged, negatively charged, or neutral

depending on the pH of the solution

▪ The Lemke method uses functional groups to predict the solubility of a molecule

o The more hydrogen bonds that are available to form between a drug and water,

the more soluble the drug is

o Think of it as the more functional groups that are there to make hydrogen bonds,

the more soluble the molecule

o When the molecule is ionized, it also becomes highly soluble

▪ H-O, H-N, and H-F bonds are very polar

▪ A molecules basicity/acidity is also based on steric hinderance

o Ex) Secondary and tertiary amines are more basic than primary amines because

they are attached to electron donating groups

o Secondary amines are more basic than tertiary amines because there is less

steric hinderance