- single bonds - formed by hybrid orbitals - free rotation around this bond

- double bonds - formed by overlapping P orbitals - no free rotation around this double bond

Lecture 1 (Intro to MedChem) Flashcards by Sam Myers

What is a lead compound?

A lead compound is like the first draft of a drug. It has the correct pharmacological effect but it is not perfect. It most likely needs to be tweaked to obtain the most optimal and effective drug function.

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How are drugs improved?

By using a SAR (structure activity relationship) we can turn lead compounds into safe and effective drugs.

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Two types of SARs?

Quantitative (QSAR)
Qualitative (SAR)
-this is the only one we are concerned with

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How is a QSAR used?

Uses a mathematical relationship between PHYSICOCHEMICAL PROPERTIES to their pharmacological activity to predict the most potent structure.

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Why won’t we be studying QSAR?

Because it cannot easily be extrapolated to new drugs. It requires extensive research for each drug.

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How is a SAR used?

-uses the relationship of the STRUCTURE (arrangement of the functional groups) and the pharmacological activity of the drug

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What are the chemical properties of drugs we need to consider?

placement of covalent bonds
EN
electron effects of functional groups
- ED (electron donating)
- EW (electron withdrawing)

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What drug properties are going to be affected by different things?

potency absorption
distribution
metabolic profile

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Describe sigma bonds

single bonds
formed by hybrid orbitals
free rotation around this bond

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Describe pi bonds

double bonds
formed by overlapping P orbitals
no free rotation around this double bond

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Define EN

ability to attract electron density

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How does EN increase on the periodic table?

to the right and up it increases

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What 2 ways can electron density move through a molecule?

resonance

- induction

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Define resonance

movement of electron density through pi bonds (conjugated system)

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Every 1st bond is ____?

sigma

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Every 2nd or 3rd bond is ___?

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What are sigma bonds made from?

hybridized orbitals (sp)

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What are pi bonds made from?

leftover p orbitals

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Define induction

movement of electron density through sigma bonds (saturated carbons)

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How do you determine whether a functional group with be ED or EW?

Depends on:

EN
presence of lone pair electrons
multiple bonds (geometry of the molecule)

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Electronegative atoms with a lone pair (excluding halogens) are __ through _________.

resonance

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Alkyl groups - the more branched, the more _____.

donating

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Attached group with a double bond O or N or triple bond N are __ through __________.

resonance

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pKa _____ for acids

low (inverse of Ka)

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Ka ____ for acids

high (if they dissociate there is more of the ions than the acid - so a bigger number/ smaller number = high number)

pKa ____ for bases

high (inverse of Ka)

Ka ______ for bases

low (bases don't like to dissociate so there would be less of the ions than the base - small number/big number = low number)

Ratio of ionization of a weak acid is what ratio?

[HA] / [A-] | unionized: ionized

Ratio of ionization of a weak base is what ratio?

[HB+] / [B] | ionized: unionized

To maximize ionization of HA to A-

pH > pKa

To minimize ionization of HA to A-

pKa > pH

To maximize ionization of B to HB+

pKa > pH

To minimize ionization of B to HB+

pH > pKa

We use pKa to measure ___ ________.

drug ionization

We always assume the solvent is _____?

WATER BITCHES

When we talk about the pKa of a base we will most likely be talking about ??

primary, secondary, or tertiary amines

What is the difference between primary, secondary, and tertiary amines?

Primary: The N is attached to 1 R group and 2 H's Secondary: The N is attached to 2 R groups and 1 H Tertiary: The N is attached to 3 R groups

How does the scale of basicity go for amines?

Secondary > Primary > Tertiary

What is a substituent?

-an atom or group of atoms substituted in place of a HYDROGEN on the parent organic compound

Describe alkanes

-tetrahedral -sp3 hybrid -bond angle 109.5 C-C bond length 1.5A -non-polar (hydrophobic) -ED ALWAYS

Describe alkenes

-planar -sp2 hybrid -bond angle 120 C=C bond length 1.3A -non-polar (but depends what R groups are) -usually ED but can be EW depending on substituents

Describe alkynes

- sp hybrid - bond angle 180 - C=-C (triple bond) bond length 1.2A - non polar (hydrophobic) - mostly EW

Are alkanes and alkenes water soluble?

No way jose

What happens when an alkane or alkene gets larger or more branched?

Becomes less hydrophilic or more lipophilic

Halogenated hydrocarbons are generally less _____ than the alkyl form.

hydrophilic

Halogenated hydrocarbons are ______.

hydrophobic

Halogens on saturated hydrocarbons are ___ by _______.

EW | induction

Why are alcohols more water soluble?

They have an OH group (hydroxyl) which increases polarity and therefore makes it more water soluble because water is also a polar molecule.

Describe the hybridization and geometry of alcohols

sp3 hybridization | tetrahedral

Alcohols from bonds with water through what type of bond?

Hydrogen bond

How is an OH ED?

through resonance

How is an OH EW?

through induction

T or F: an alcohol only accepts hydrogen bonds

FALSE alcohols are H bond donors and acceptors

Why do alcohols have a permanent dipole?

EN oxygen positive hydrogen *those two bad boys result in a permanent freaking dipole

With increasing length of hydrocarbon chain on an alcohol - how does that affect solubility?

decreases solubility

Are alcohols very acidic?

NO WAY JOSE

Does alcohol solubility depend on location of OH?

yeah man

Describe a phenol

-special type of alcohol

Are phenols generally more acidic (more acidic means LOWER pKa) than aliphatic alcohols? *slide 37

you bet your ass they are :D

aromatic hydrocarbons are ________

hydrophobic

SH (sulfhydryl) groups are ALWAYS __?

ED (sulfur is not very EN so it's not going to withdraw - it will donate)

SH group is _____ polar

weakly

RSH is more _____ than ROH

acidic

R-O-R is a ??

ether

R-S-R is a ???

thioether

ethers and thioethers are weakly _____

polar

SR (thioalkoxy) is ____

OR (alkoxy) is ____

ED/EW

sulfoxide is always ___

sulfone is always __

Describe the hybridization and geometry of aldehydes and ketones

sp2 hybridization | planar

aldehydes and ketones are always __

EW (they have an oxygen which is highly EN) - so therefore it will withdraw electrons

aldehydes and ketones are in rapid equilibrium with ____ to form hemiketals and hemiacetals

alcohol

_____ have an sp3 tetrahedral N centre

amines

Are amines basic or acidic?

basic

Are amines polar?

yeah man

The N of amines are basic due to what?

free lone pair of electrons

describe the hybridization and geometry of carboxylic acids (RCOOH)

sp2 | planar

Are carboxylic acids polar?

yes

neutral form of carboxylic acids are ____

anionic form of carboxylic acids are ____

Are esters (RCOOR) polar?

yes

Are esters (RCOOR) ED or EW?

esters are susceptible to _____

hydrolysis

What are esters frequently incorporated for?

To facilitate absorption of carboxylic acid drugs (they act as a pro drug)

Describe hybridization and geometry of amides

sp2 | planar

are amides polar?

heck yes (napoleon dynamite voice)

Is the N of an amide (RCONHR) basic?

NO (because lone pair of electrons forms resonance structure and therefore is not available to accept a proton) * N of amine = basic * N of amide = not basic

The H of RCONHR (amide) is usually ___?

only very weakly acidic

Are amidines and guanidine's polar?

YES

In neutral form amidines are ___

In neutral form guanidine's are ___?

weakly EW and weakly ED due to electronegative nature of the N *see slide 48 for details of structure

In ionized form, both amidines and guanidine's are ___

Are amidines and guanidine's less basic than amines?

No, they are more basic.

Are Nitro (RNO2) highly EW or ED?

EW all the way

Is the negative charge on the O in a nitro (RNO2) able to accept a proton?

no way man

Describe hybridization and geometry of sulfonic acids and sulfonamides

sp3 | tetrahedral

T or F: sulfonic acids and sulfonamides are highly polar and EW

true true true

Heterocycles usually contain what 3 elements?

S, O, and N

Drugs with a 3 or 4 membered ring (heterocycle) are usually ???

strained and unstable (like me after a night of drinking)

What are the requirements for a structure to be aromatic?

cyclic planar 4n+2 delocalized conjugated (every atom in the ring has p orbitals capable of forming pi bonds)