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Flashcards in Introduction Deck (65):

What is medicinal chemistry?

A large field that encompasses many disciplines (synthetic organic chemistry, enzymology, biochemistry metabolism, etc.)


What do medicinal chemists do? What do they produce?

Medicinal chemists discover new chemical entities with pharmacological effects and, by a process of chemical modification, produce lead compounds and from the lead compounds produce new, safe and effective drugs to treat disease


What's a chemical entity?

Any (likely organic) chemical


What is a lead compound?

A chemical compound with the desired pharmacological effect that can be modified chemically to improve its potency, absorption, distribution, metabolic profile (or any aspect of the drug)


How do you improve a drug?

By utilizing the knowledge of, or determining the Structure Activity Relationship (SAR), a medicinal chemist can turn lead compounds into safe and effective drugs


Describe the quantitative SAR. Why is it important?

Generating a mathematical relationship between physicochemical properties of a series of compounds and their pharmacologic activity. In this case the "compounds" are modifications to the lead. This mathematical relationship can predict the most potent structure


Describe the qualitative SAR.

The relationship between the structure and the pharmacological activity of the drug, i.e., how arrangement of functional groups on the drug molecule effect pharmacological activity (absorption, secretion, etc.)


What is an important chemical property of drugs?



What is electronegativity? Why is it important?

Electronegativity is a measure of the tendency of an atom to attract a bonding pair of electrons (basically: what would the electrons do?)
Electronegative atoms can polarize a molecule resulting in a permanent dipole


How do functional groups affect electrons?

Electrons can move around (delocalize) depending on functional groups.


What are the two ways that electrons move?

There are two ways electron density can move through a molecule: resonance and induction


Define resonance

The movement of electron density through pi-bonds (i.e., though alliterating single and double bonds aka conjugated systems)


Define induction

The movement of electron density through sigma-bonds (i.e, through saturated carbons)


How do functional groups affect the movement of electrons (through resonance and/or induction)?

A functional group may be electron donating (ED) or electron withdrawing (EW) depending on if ED or EW happens by resonance (pi-bond) or by induction (sigma-bonds). Therefore the same functional group may be ED or EW depending on if it happens through pi or sigma-bonds.


Besides the type of bonds, what else affects ED and EW?

ED and EW also depends on electronegativity, the presence of lone pair electrons, multiple bonds and the geometry of the molecule


In resonance, how does delocalization happen?

Delocalization happens through a series of pi-bones = conjugation. There's a hydride structure, which has partial double bon character


In induction, how does delocalization occur?

Delocalization happens because of the distribution of electron density over the molecule through sigma-bonds


Where do we find EW inductively but ED by resonance?

In electronegative atoms with a lone pair (-OH, -NH2)
Exceptions are halogens, which are EW but usually do not participate in ED


Where do we find ED by induction?

Alkyl groups, the more branched, the more donating


Where do we find EW only by induction?

Atoms with no lone pair of electrons but have partial positive charge or a charge of +1 (-CF3, -NH3+, halogens)


Where do we find EW inductively and by resonance?

Attached group with a double bond O or N or triple bond N (NO2, CN, SO2R, SO2NHR)


Where do we find EW or ED by resonance?

When attached to a benzene ring


What is acid/free acid?

Protonated acid (HA)


What is conjugate base?

Deprotonated acid (A-)


What is free base?

Deprotonated base (B)


What is conjugate acid?

Protonated base (HB+)


What is the ratio ionization based on?

The pKa and the pH of the solution


To estimate the ratio of ionization, to significantly ionize HA to A-:

Need pH > pKa


To estimate the ratio of ionization, to minimize the ionization of HA to A-:

Need pH


To estimate the ratio of ionization, to significantly ionize B to HB+:

Need pH


To estimate the ratio of ionization, to minimize the ionization of B to HB+:

Need pH > pKa


What happens when pH = pKa

You get 50% ionization


What happens when a drug contains both HA and B in the structure and the pKa of HB+ is greater than the pKa of HA?

Example: glycine, where the pKa of HA = 2.5 and pKa of HB+ = 9. In solid form or water at pH 7, it is a zwitterion (positively and negatively charged). In strong acid (pH 9), it is negatively charged


What do we mean when we talk about the pKa of a base?

We will almost always be talking about a 1st, 2nd or 3rd amine, and specifically the pKa of its conjugate acid


Carboxylic acids are weak acids. Explain

Both the inductive effects in the neutral form and the resonance effects in the ionized form explain why its COOH proton is acidic
Inductively withdraws electrons from H, thus making the H acidic.
A stable carboxylate anion is resulted after H+ departs. The negative charge is stabilized through resonance


Why are acids and bases important in medicinal chemistry? Give some examples

Acids and bases are commonly used to ionize and make salts of drugs. Drugs are usually marked in a salt form because they are easier to make into a solid dosage form and they dissolve more readily in water. Unionized drugs are typically oils and are not easy with which to work.
Example: Warfarin sodium (warfarin + NaOH) is much more water soluble than warfarin
Example: Pseudoephedrine HCl


What are the advantages to salts?

Drugs is water soluble and will dissolve in the gut
The free acid/base is often an oil and the conjugate base/acid is a crystalline form
Oils are notoriously impossible to tablet and are often hydroscopic and therefore very difficult to measure by weight
The conjugate acid/base can be weighed and tableted more easily
In many cases the conjugate acid/base as a solid crystalline form is more stable while the free base/acid as an oil is less stable


What is a substituent?

An atom or group of atoms substituted in place of a hydrogen atom on the parent organic compound (very important).
Also known as moiety, side-chain, functional group, group, or branch.


Describe alcanes

Tetrahedral carbon centre
sp3 hydrbidization
Bond angle: 109.5º
C-C bond length: 1.5 A or 150 pm
Non polar
Always ED
Methane, Ethane, Propane
Substituent: Methyl, Ethyl


Describe alkenes

Planar geometry
sp2 hybridization
Bond angle: 120º
C=C bond length: 1.3 A or 130 pm
Non polar
ED/EW depending on substituents
Ethene, Propene, Butene
Substituents: Ethenyl, propenyl, butenyl


Describe alkynes

sp hydridization
Bone angle: 180º
Bond length: 1.2 A or 120 pm
Non polar
Mostly EW


Describe alkanes and alkenes

They cannot form ionic, hydrogen or ion-dipole bonds with themselves or water, only van der Waals is possible
They cannot break and form bonds between and with water so they are not water soluble
The larger or more branched the alkyl, the less hydrophilic or more lipophilic the group becomes
Halogenated hydrocarbons (CH3F, CCl4) are generally less hydrophilic than the alkyl form


Describe alcohols

They can form H-bonds with water and are polar, so they therefore increase solubility
They can be ED via resonance or EW via induction
They are H-bond donors and acceptors
sp3 hybridization
Tetrahedral geometry
There is a permanent dipole
Not very acidic


What are phenols?

A special type of alcohol (alcohol + benzene)
Generally they are more acidic than aliphatic alcohols (pKa between 9-10) but it depends on other substituents


Describe aromatic hydrocarbons

Names: phenyl, naphthyl
ED/EW depending on substituents


Describe thiols and thiophenols

SH (sulfhydryl) group is only weakly acidic
SH is always ED
R-SH is more acid than R-OH
E.g., CH3-SH (methanethiol or methyl mercaptan)


Describe Ethers and thioethers

Only weakly polar
O-R (alkoxy) is ED/EW
SR (thioalkoxy) is ED
E.g., Diethyl ether aka ethoxyethain, methoxybenzene, diethyl thioether


Describe sulfoxides

Always EW
S centre is tetrahedral
Lone pair of electrons
Chiral if R doesn't equal R'
Highly polar
Famous solvent: DMSO


Describe sulfones

Always strongly EW
S centre is tetrahedral
Highly polar


Describe aldehydes and ketones

Carbonyl (C=O) is polar, can form H-bonds with water (dipole-dipole interaction)
Always EW
They are in rapid equilibrium with alcohol to form hemiacetal and hemiketal


Describe amines

An important functional group
Polar, can form H-bonds with water (dipole-dipole or ion-dipole)
Neutral forms of amines are ED (resonance) and EW (induction)
The N of amine is basic (loan pair)


Describe carboxylic acid

A very important group
Polar, H-bonding, dipole-dipole, ion-diple
EW (neutral form), ED (anion form)
Acidic, readily deprotonated at physiological pH


Describe esters

Important group
Polar, H-bonding with water
Always EW
Susceptible to hydrolysis (major route of metabolism, catalyzed by esterases; frequently incorporated to facility the absorption of carboxylic acid drugs - act as a pro-drug


Describe amides

Important group
Polar, H-bonding with water, dipole-dipole
Always EW
The N is not basic (forms resonance structures)
VERY weakly acidic
Neutral at physiological pH


What are nitriles and carbonates similar to?

Similar properties to esters


What are carbamates similar to?

Properties in between esters and amides


Describe ureas

Properties similar to amides
Very stable


Describe amidines and guanidines

Highly polar, H-bonding, dipole-dipole, ion-dipole with water
In neutral form, amidine is EW but guanidine is weakly ED and weakly EW (due to electronegative nature of N)
In ionized form, EW
Multiple tautomeric forms are possible
More basic than amine. Usually fully protonated at pH 7.4 (depends on substitution)
sp2 hybridization


Descibre Nitro

Although nitro group is charged, it is only slightly polar (electrically neutral because of + and - charges)
Highly EW
The negative charge on O is unable to accept a proton


Describe sulfonic acids

Properties similar to carboxylic acids
Highly polar
More acidic than carboxylic acids


Describe sulfonamides

Properties similar to amides
More acidic than amides


What are the requirement for aromaticity?

Delocalized conjugated (every atom in the ring has p-orbitals that can form pi-bonds and every atom is sp2 hybridized)
Number of p-orbitals capable of forming pi-bonds satisfies this relationship: 4n+2 where n=1,2,3


Describe the aromaticity charge distribution

There is potential for interaction between aromatic groups. This is not technically a dipole-dipole interaction because the aromatic ring has more than two poles.


What is aromatic stacking interactions?

Aromatic stacking interactions are also called pi-stacking interactions. They are important for drug receptor interactions and for protein folding and DNA and RNA interactions


What are the different types of aromatic stacking interactions?

T-shaped stacking interaction aka Edge to face interaction
Parallel displaced interaction
Sandwich interaction