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What is electronegativity?

How strongly atoms attract bonding electrons to themselves.

If a bond is polar?

It has a dipole moment

What is electronegativity?

How strongly atoms attract bonding electrons to themselves.

If a bond is polar?

It has a dipole moment

If Nitrogen, Florine, Oxygen, or Chloride is bonded to a non-metal other than itself

Then the bond will have a dipole moment

Hydrogen bond donators

Are hydrogen atoms attached to N or O, they play a key role in hydrogen bonding with water

Non polar covalent

equal sharing of electrons ( Cl2, CS2, or C-H)

Polar covalent

unequal sharing of electrons (NH3, H2O)

Ionic Bond

Formed when one or more electrons are transferred from one atom to another. ( NaCl or MgCl2)

Polar covalent bond

δ+ (the atom with the lesser share of electrons), δ-
(the atom with the greater share of electrons)

Will a molecule always have a dipole moment even if it contains polar covalent bonds

No, always look at its geometry

Hydrophilic compounds

Compounds that interact with water are polar or carry an electric charge (positive or negative)

Lipid soluble (lipophilic)

Are water-insoluble (non-polar) Ex: hydrocarbons.

Delta H(enthalpy)

exothermic, energetically favorable

Negative delta G

spontaneous, exergonic, starts the reaction in a compound

Positive delta S

more disorder, hydrophobic effect

S character

sp3 = 25%, sp2 = 33%, sp = 50% (remaining percent is p character)

Amphipathic

having both a hydrophilic (polar) region and a hydrophobic (non-polar) region

Why are drugs Amphipathic?

In order to pass through the cell membrane bilayer (non-polar) and then dissolve in water (polar).

Phospholipids

A molecule that is a constituent of the inner bilayer of biological membranes, having a polar, hydrophilic head and a nonpolar, hydrophobic tail.

Individual water molecules forming a cage have less…

entropy (disorder) b/c they are more highly organized.

Acid

compound that donates a proton (H+) to water

Base

A compound that can accept a proton from water (BH+)

Protonated (P)

the compound with the extra hydrogen atom

Unprotonated (U)

The compound with one less hydrogen atom

If the neutral (unionized) specie of the pair (P and U) is donating (losing) a proton it would be considered…

An acid

If the neutral (unionized) specie of the pair (P and U) is accepting a proton it would be considered…

A base

A weak acid and base…

will not ionize 100%, both the protonated and unprotonated compounds will co-exist in the solution

Which is the protonated compound in this example?

CH3COOH + H2O = (CH3COO-) + (H3O+)

CH3COOH, b/c it starts with the extra H+ and its also considered neutral since it doesn't have a charge.

Which is the unprotonated compound in this example?

CH3COOH + H2O = (CH3COO-) + (H3O+)

CH3COO- , b/c it donated its H+ to water

Organic acids and bases are generally classified as…

WEAK, they do not ionize completely.

The larger the numerator in a Ka/Kb means…

the acid or base is stronger, it produces more products (ionized), more acidic/ basic

The smaller the pKa value of an acid means…

the stronger the acid

The smaller the pKb value of a base means…

the stronger the base

pKa + pKb =

14

pOH + pH =

14

The Golden Equation

P/U = 10^(pKa - pH)

For acids: P = HA (unionized) , U = A- (ionized)
For bases: P = BH+ (ionized) , U = B (unionized)

Golden Equation for an acid:

HA/A-

Golden Equation for a base:

BH+/B

The LARGER the "pKa" value listed for a BASE…

the STRONGER the BASE

Where will an acid be more unionized. In the stomach pH= 1.5 or in the blood pH = 7.4 ?

In the stomach b/c the lower pH (more H+ ) of the stomach favors formation of more HA, the protonated form of the acid, which would be formed in the blood.

Lowering the pH of the surrounding environment favors the formation of…

the protonated form (HA/unionized) more than previously.

Absorption through a biological membrane would need…

a compound that is uncharged (neutral) to 100% be absorbed

When the pH is lowered for an acid…

the equilibrium will be driven to the left favoring the formation of HA (protonated).

Adding more protons (lowering the pH of the environment) causes what to a base?

BH+ to form more which is the pronated/charged form of a base. In this case the equilibrium is shifting to the right.

At a higher pH a base will…

favor the unprotonated/uncharged form (B)

Where will a base be more unionized (neutral). In the stomach pH= 1.5 or in the blood pH = 7.4 ?

In the blood b/c at a higher pH the base will become more unprotonated (B) which is the unionized form for a base.

Lowering a the pH in a environment favors…

protonation of either an acid or base relative to the previous pH. HA (unionized) for an acid, and BH+ (ionized) for a base.

pH>pKa

unprotonated will be predominant ( A- for an acid; B for a base)

pH<pKa

protonated will be favored (HA for an acid; BH+ for a base)

If both the pH and the pKa are equal…

then there will be equal amount of protonated and unprotonated species present, 10^0=1

An acid in a acid becomes…

Neutral

A base in a base becomes…

Neutral

An acid in a base, or a base in an acid becomes…

Ionized (charged)

Non-polar substances are able to be absorbed through the lumen of the renal tubules back into the bloodstream due to…

The walls of the renal tubules are made up of cells with their lipid member which are more permeable to UNIONIZED (uncharged) molecules.

Acids/Bases in their neutral (uncharged) forms can be…

Reabsorbed

Sodium Bicarbonate (NaHCO3)

can be used to alkalinize the urine.

By raising the pH of the lumen of the renal tubules (where the environment is neutral) with sodium bicarbonate during a overdose of an acidic drug…

We can increase the fraction of the drug in its ionized form (A-) b/c the unprotonated form of the species is favored as a result.

By lowering the pH of the lumen of the renal tubules with ammonium chloride during a overdose of a basic drug…

We can increase the fraction of the drug in its ionized form (BH+) b/c the protonated is favored as a result.

Acids/Bases in their charged (ionized) form…

can not be absorbed by a membrane

An increase in the ionized form of a drug…

decreases REABSORPTION, thus enhancing renal elimination.

Acetylsalicyclic acid (aspirin) can do great harm to the body in overdose, in fact, it can be lethal. Suppose a patient arrives in your hospital's emergency room who has tried to commit suicide by swallowing a whole bottle of aspirin tablets he found in his medicine chest. What might you want to do to detoxify the patient?

Administer sodium bicarbonate to alkalinize (raise pH level) the patient's urine. This will increase the fraction of aspirin in its negatively charged (A- ) form. This form is not reabsorbed from the renal tubule, and will remain in the urine to be excreted. Blood levels of aspirin will consequently decrease

Is Nicotine an acid or base?

A base

Morphine is frequently administered as morphine sulfate. Is morphine an acid or a base?

The negatively charged counter-ion of morphine has "ate" in its name (i.e. sulfate ) soMorphine is a base. Its protonated (BH+ ) is positively charged

Losartan is often administered as "losartan potassium." Is losartan an acid or a base?

The positively charged counter-ion is K+ so Losartan is an acid. Its unprotonated (A- ) is negatively charged

If the name of a salt is sodium valproate, are we dealing with an acidic or a basic drug?

The "sodium" in the name represents "Na+", it is merely the positively-charged counterion in the salt. That means that "valproate" must be negatively, charged meaning it's an acidic drug.

Phenobarbital (weak acid): pKa = 7.4; Acid urine: pH = 5.4

P/U= 10^(7.4-5.4)= 10^(2)= 100.

100x as much unionized (Lipid Soluble (nonpolar) /HA) phenobarbital in the urine which would be reabsorbed

Phenobarbital (weak acid): pKa = 7.4; Alkaline urine: pH = 8.4

P/U=10^(7.4-8.4)= 10^(-1)= 1/10.

10x as much unprotonated (lipid insoluble/polar)
A- meaning phenobarbital will be excreted

Kenamycin (weak base): pKa = 7.2; Acidic urine: pH = 6.2

P/U=10^(7.2-6.2)=10^(1)=10

10x as much protonated (lipid insoluble/ polar) BH+ meaning kenamycin will be excreted

Kanamycin (weak base): pKa = 7.2; Alkaline urine: pH = 8.2

P/U= 10^(7.2-8.2)=10(-1)=1/10

10x as much unprotonated (lipid soluble/ nonpolar) B meaning kenamycin will be reabsorbed

An organic acid contains a functional group whose…

Neutral form can lose (donate) a proton. Due to the loss of the proton, the substance now bears a negative charge (the anion).

The proton lost in an organic acid will be covalently attached to either…

Oxygen, nitrogen, or sulfur. (O-H, N-H, S-H).

These bonds are considered to be acidic

O-H, N-H, S-H

resonance delocalization

occurs in aromatic rings and conjugated double bonds, this stabilizes the compound

To decipher whether a compound is an acid

one should think in terms of the product (conjugate base) resulting from the loss of the proton.

If the negatively charged species (anion) that forms is stable then…

The more stable the negative charge is the stronger the acid.

Why is phenol an acid while (alicyclic) cyclohexanol is not?

Due to the resonance delocalization of the negative charge from the oxygen atom of the phenoxide anion increases stability.

If the hydroxyl group in the cyclohexanol (and most alcohols) were to lose its proton…

then the negative charge on the oxygen atom thats produced will not be able to delocalized meaning there wouldn't be any mechanism to stabilize the charge. Since cychexanol will not give up its proton it's NOT acidic.

resonance stabilization/delocalization

plays a major role in determining whether a compound is acidic or not

An anion that can be further delocalized means…

theres an increase in stability which equals to a stronger acid

Can you explain why the pKa of picric acid (structure to the right) is so drastically different from that of the other three phenols listed below (i.e., why is picric acid a much stronger acid ?)

Because of the multiple resonance structures that can stabilize the acid

carboxylic acid

is acidic

Why are carboxylic acids more acidic than most phenols?

Even though phenols have more resonance structure the negative charge ends on a carbon atom while in a carboxylic acid the negative charge ends on a oxygen atom (more electronegative)

Amides

Should not be considered acidic or basic

Imides

R1 must be H in order for it to be acidic

Sulfonamides

R2 or R3 must be H in order for it to be acidic

In the resonance of a sulfonamide…

The negative charge on the N can be delocalized to either of the two oxygen atoms. While this does make it stable most sulfonamide are still weaker than carboxylic acids.

Cyclic Sulfonamides

contains two sulfonamide moieties attached to a ring and in a ring, and is still acidic

Sulfonylureas

Is more acidic than sulfonamides because once the nitrogen becomes negatively charged it can be delocalized to either oxygen atom attached to the sulfur atom and to the oxygen attached to the carbon atom.

Is sulfonic acid stronger than carboxylic acid? Why?

Yes, because once a negative charge forms on the oxygen atom of the sulfonic acid it can be delocalized to either of the two sulfonyl oxygen atoms making it more stable than carboxylic acid

Thiols

Once the thiol loses (donates) its proton the negative charge ends up on the sulfur which is a larger atom than oxygen (spreads over a larger surface area)

The structure of ascorbic acid is shown below. Note that the compound has two alcoholic OH groups attached directly to the ring. We just stated that aliphatic/alicyclic alcoholics are not acids. Then why is ascorbic acid acidic?

a certain OH group within the molecule is acidic because once this OH group loses (donates) its proton and the negative charge forms on the oxygen atom of the anion, it can be delocalized (and hence, stabilized) via resonance with the carbonyl oxygen.

An organic base…

is a neutral substance that can accept a proton

Usually in medicinal chemistry the atom that accepts the proton is…

a nitrogen atom which bears at least one lone pair of electrons, this forms a positive charge on the nitrogen (N-H)

What can increase the availability of a lone pair?

an increase in electron density (usually on the nitrogen)

Any process that decreases or withdraws electron density from the lone pair of electrons on the nitrogen makes…

the lone pair LESS available to attract and pick up the proton making the substance less basic/weaker

When spotting a nitrogen atom in a compound ALWAYS…

look to see what is immediately bonded to it in all directions. This will determine if the nitrogen atom is a component of an acid, base, or neither.

An aliphatic amine

is an amine in which the nitrogen atom bears a single lone pair and where all the atoms attached to it are either a hydrogen atom or a saturated carbon atom (the carbon has a single bone with all of its substituents)

Depending on how many saturated carbon atoms are attached to the nitrogen , basic aliphatic amines are classified as…

Primary, Secondary, or Tertiary

Strength of aliphatic amines (strongest to weakest)

2>1>3 (if, and only if, al three are indeed ALIPHATIC amines

Alicyclic amines

substances in which the nitrogen atom is incorporated into a ring system and all bonds to the nitrogen are hydrogen or a saturated carbon atom. They are BASIC

Aromatic amines

are considered very weak bases b/c of an unsaturated carbon atom adjacent to the nitrogen atom, this means the lone pair of electrons on the nitrogen are less available to attract a proton