Pharmaceutics Exam 1: Functional Groups and Stereochemistry

intermolecular force vs intramolecular force

inter: forces that exist between molecules

intra: forces that exist between atoms within molecules

strongest intermolecular force

ionic interactions

ionic interactions

exist between ions (salts/charged species)

strongest type of intermolecular force

ion-dipole forces

exist between an ion (charged species) and a dipole

hydrogen bonds

intermolecular attractions that exist between the hydrogen of one species and the oxygen/nitrogen/fluorine of another species

H-bonds are a type of dipole-dipole interaction (the strongest type), and are attractions not actual bonds

dipole-dipole interactions

attractions that exist between a partially positive portion of one species and a partially negative portion of another species

these are attractions and not actual bonds

van der Waals interactions

weak attractive forces between uncharged molecules

hydrophobic interactions (think "clumping") are the most commonly discussed

the number of intermolecular forces between molecules is ____ proportionally to the boiling point

directly

(increasing the number of forces increases the boiling point because more bonds must be broken, requiring more energy)

the molecular weight of a molecule is ____ proportionally to the boiling point

directly

electron-donating groups

substituents that "push" electron density toward a functional group to increase electron density --> more likely to accept a proton

ex. alkyl groups

electron-donating groups and acid/base character

decrease in acidity and increase in basicity

EDGS increase electron density, which increases the ability to accept a proton (ie. positively-charged proton is attracted to a more "negative" species)

electron-withdrawing groups

substituents that "pull" electron density away from a functional group to decrease electron density (disperse the cloud) --> more likely to donate a proton

ex. benzene, halogens, -SO2, -NO2

electron-withdrawing groups and acid/base character

increase in acidity and decrease in basicity

EWGs disperse electron density, making the species more likely to donate an electron ("floating" -H is less-attracted to the less-negatively charged species)

electropositivity

tendency to donate electrons (EDGs)

electronegativity

tendency to withdraw/disperse electrons (EWGs)

aromatic hydrocarbons

contain a benzene ring or a derivative of a benzene ring

aromatic hydrocarbons are ____ groups (in terms of electrons) because....

electron-withdrawing

they have a high electron density that results in a delocalization of electrons (they pull electrons toward themselves, making the R-group they are attached to more electropositive)

When aromatic hydrocarbons are metabolized, they are ____ by CYP45s to become more ____

hydroxylated

water-soluble

Why can aromatic hydrocarbons be carcinogenic?

the process of hydroxylating AHCs produces an epoxide intermediate, which experiences a lot of ring strain and is therefore highly reactive (toxic) to nucleophiles such as DNA

alcohols

organic compounds containing hydroxyl groups

in vitro, alcohols are susceptible to ____ reactions

oxidation

Why is methanol more toxic than ethanol?

oxidation of methanol by alcohol dehydrogenase produces formaldehyde (toxic), which is then metabolyzed to formic acid (also toxic)

oxidation of ethanol by ADH produces acetylaldehyde (toxic-ish), which is then metabolyzed to acetic acid (vinegar)

What is the treatment for methanol poisoning and why?

large amounts of ethanol, because ethanol competes with methanol for oxidation by alcohol dehydrogenase, preventing methanol from being converted to formaldehyde/formic acid

Why is 1-butanol more water-soluble than 2-butanol?

1-butanol experiences more van der Waals interactions than 2-butanol

the -OH group in the middle of 2-butanol disrupts vdWaals, which makes it less hydrophobic and therefore more water-soluble

phenols

characterized by an -OH attached to a benzene ring

Are phenols acidic or basic and why?

weakly acidic

the negative charge on the oxygen after hydrogen donation is stabilized by resonance and the electron-delocalizing characteristic of aromatic hydrocarbons (electron-withdrawing character makes the O- charge of the conjugate acid less negative)

Why does phenol have a higher boiling point than cyclohexanol?

the constant conversion of cyclohexanol between chair and boat conformations results in less ability for hydrogen bond formation

phenols are readily ____ to guanine when exposed to air

oxidized

Vitamin E and phenols

Vitamin E is readily oxidized, so it acts as a shield (antioxidant) to prevent the oxidation of phenols

ketone

carbonyl group (C=O) is within carbon skeleton

aldehydes

carbonyl group (C=O) is at the end of the carbon skeleton

Can ketones and aldehydes hydrogen bond?

they cannot hydrogen bond, but can dipole-dipole bond

tautomerization

conversion between a keto (left) and enol (right) form

a C=C bond is formed with the enol (ene + ol --> C=C + an -OH)

What is the affect of tautomerization in relation to acid-base character?

tautomerization makes the molecule more acidic

Increasing the length of the hydrocarbon chain of ketones and aldehydes results in a(n) ____ in boiling point and a(n) ____ in water solubility

increase

decrease

(more vdWaals possible)

Are ketones and aldehydes susceptible to air oxidation?

aldehydes are susceptible --> carboxylic acid

ketones are generally NOT because it is difficult to break a C-C bond (although they can be oxidized when attached to benzene)

hemiacetal

formed in acidic conditions when an alcohol is introduced to an aldehyde/ketone

glucuronic conjugates are ____

aldehydes

The reason barbituric acid is approximately 3 pKa units more acidic than phenobarbital is due to:

A. The electron-withdrawing character of the benzene ring

B. The electron-donating character of the benzene ring

C. Its ability to tautomerize to form an enol

D. Its ability to accept a proton

The reason barbituric acid is approximately 3 pKa units more acidic than phenobarbital is due to:

A. The electron-withdrawing character of the benzene ring barbituric acid does not have a benzene ring

B. The electron-donating character of the benzene ring this would actually make barbituric acid more basic, if it even had a benzene ring

C. ITS ABILITY TO TAUTOMERIZE AND FORM AN ENOL

D. Its ability to accept a proton accepting a proton is a characteristic of bases

Are primary or tertiary alcohols more likely to be oxidized?

primary are more likely to be oxidized

tertiary alcohols are more stable

also, oxidation of alcohols results in the formation of a C=O bond and requires the C-H bond between the -OH-adjacent carbon to be broken, a bond which is not present in tertiary alcohols

amines

organic compounds with an amino group

"Vitamin" = life-giving amine

Are amines acidic or basic?

weakly basic

primary amine

an amine where the nitrogen atom is attached to one alkyl chain

secondary amine

an amine where the nitrogen atom is attached to two alkyl chains

tertiary amine

an amine where the nitrogen atom is connected to 3 carbon atoms

quarternary amine

a configuration in which nitrogen has four bonds with other atoms --> positively-charged nitrogen

quarternary amines (ammonium salts) are unreactive/stable and "neutral"

rank the basicity of primary, secondary, and tertiary ethylamines

secondary > tertiary > primary

tertiary ethylamines experience more steric hindrance than secondary --> less basic

however, tertiary are more basic than primary because the ethyl groups "pump" electrons in towards the nitrogen, making it more likely to accept a proton than primary

rank the basicity of primary, secondary, and tertiary methylamines

secondary > primary > tertiary

secondary methylamines have more e-donating groups (-CH3) than primary amines --> makes the nitrogen more electronegative, and therefore more likely to accept a proton

tertiary methylamines experience steric hindrance, and so are less likely to accept a proton

How are quarternary ammonium salts used for targeted drug action?

quarternary ammonium salts have a permanent positive charge, and so cannot pass through membranes

ex. inhaled quarternary ammonium salts will stay in the lungs

Can amines be dealkylated?

secondary and tertiary (NOT primary) amines can be dealkylated (-CH3 groups removed)

**very important**

Can amines be oxidized?

secondary and tertiary (NOT primary) amines can be oxidized to form an N-oxide

**very important**

primary amines cannot be oxidized

primary amines can be ____ with pyridoxal phosphate

deaminated

methylation with methyltransferase ____ water solubility

decreases

-CH3 groups are hydrophobic

oxidation ____ water solubility

increases

conjugation to form a glucoronide ____ water solubility

increases

conjugation to form a sulfonamide ____ water solubility

increases

acetlyation ____ water solubility

decreases

Drugs that contain primary amines can have their water solubility increased by:

A. Methylation to form a secondary amine

B. Acetylation to form an amide

C. Oxidation to form an N-oxide

D. Conjugation to form a glucuronide

Drugs that contain primary amines can have their water solubility increased by:

A. Methylation to form a secondary amine decreases solubility

B. Acetylation to form an amide decreases solubility

C. Oxidation to form an N-oxide primary amines cannot be oxidized

D. CONJUGATION TO FORM A GLUCURONIDE

carboxylic acids

formic acid

carboxylic acid and toxic byproduct of methanol oxidation

Can carboxylic acids hydrogen bond with each other?

yes

results in characteristically high boiling point and water solubility

How can carboxylic acids with long alkyl chains be solvated?

the alkyl chains can vdWaals with each other to decrease solubility, so use a mixture of ethanol and H2O

the ethanol forms vdWaals with the alkyl chain, and the water forms H-bonds with the carboxylic acid

naturally-occurring unsaturated fatty acids exist in ____ conformation

cis

beta oxidation of carboxylic acids is the systematic removal of ____

two carbons at a time to form a C(n-2) chain and acetyl-CoA

esters

carboxylic acid + O-alkyl

lactones

cyclic esters

Can esters hydrogen bond with each other?

no

results in low boiling point due to weak intermolecular forces and low-ish half-life

esters are susceptible to ____ in vitro

hydrolysis to form carboxylic acid + alcohol

half-life of novocaine metabolite

1.5 minutes (contains an ester, so low-ish half-life)

(for some reason she said to remember this....)

amides

carboxylic acid + amine

lactams

cyclic amides

very reactive

Can amides hydrogen bond?

if R' or R" is a hydrogen, then yes

boiling point of amides vs esters

amides have a higher BP due to stronger intermolecular forces --> longer half-life

amides can resonate --> ion-dipole interactions (which are stronger than H-bonds)

Which has longer half-life: esters or amides?

amides

amides can hydrogen bond with each other if one of the R'/R" are a hydrogen

--> changing an ester for an amide will result in longer activity

Are amides acidic or basic?

neutral (not acidic or basic)

What is the product of amide hydrolysis?

carboxylic acid + amine

carbonate

contains a diester (C=O sandwiched between two O-R groups)

carbamate

hydrolysis --> 1 alcohol + 1 amine + CO2

urea

diamide

relatively nonreactive to esterases

metabolic products of carbonate + esterase

2 alcohols + CO2

metabolic products of carbamate + esterase

1 alcohol + 1 amine + CO2

amidine

contains an imine (C=NH) bond

guanidine

derivative of urea

very basic

Are amidines and guanidines acidic or basic?

basic

conjugate base is stabilized by resonance due to imine nitrogen (C=NH)

sulfonic acid

-SO3H

very acidic

Are sulfonic acids acidic or basic?

acidic (obviously....)

-SO2 groups are electron-withdrawing, so electron density is dispersed

sulfonamides

contains SO2 + amine

weakly acidic

Are sulfonamides acidic or basic?

weakly acidic due to resonance stability of conjugate acid

-SO2 groups are very electron-withdrawing, which counteracts the basic property of the amine group

nitro groups

-NO2

Are nitro groups acidic or basic?

neutral, but electron-withdrawing

EW nature causes other groups to be acidic

Compare the acidity of para-nitro vs meta-nitro substituents on benzoic acid

para position is more acidic due to resonance stability of conjugate acid

the negative charge on the CA is better dispersed throughout the ring for para-nitro

heterocycle

ring structure that contains at least two different elements in the ring (oxygen, nitrogen, or sulfur)

oxa- heterocycle

contains oxygen

aza- heterocycle

contains nitrogen

thia- heterocycle

contains sulfur

Why are epoxides and azirides unstable?

60-degree angle of C-O/N bonds causes significant ring strain, making them very reactive to nucleophiles

Ethylene oxide is more reactive than dimethyl ether because of:

A. The availability of the electrons on the oxygen atom

B. Ring strain

C. The difference in electron-donating ability of CH2 vs CH3

D. The difference in electron-withdrawing ability of CH2 vs CH3

Ethylene oxide is more reactive than dimethyl ether because of:

A. The availability of the electrons on the oxygen atom

B. RING SRAIN

C. The difference in electron-donating ability of CH2 vs CH3

D. The difference in electron-withdrawing ability of CH2 vs CH3

aziride ring

like an epoxide, but the O is replaced with N

beta-lactam

4-membered ring with nitrogen and C=O

ring straing --> very reactive

How can bacteria become resistant to B-lactam antibiotics?

some bacteria produce B-lactamase, which hydrolyzes B-lactams to inactivate the antibiotic