Acid and Bases

Question 1

What type of environment in which drugs exert their biological activity

Answer 1

Aqueous

Question 2

Acid

Bronsted and Lowry

Answer 2

Acid is a compound that donate a proton (H cation) to an accepter and form Conj. base
- This mean it must possess a H that is only weakly bonded to some other atom
- H form weak bonds most often with O, N, S, P
- A H that is bonded to a carbon is only acidic under special circumstances

If it doesn’t have a donatable proton, it cannot be acid

Question 3

Base

Bronsted and Lowry

Answer 3

A base is a compound which can accept a proton and must have an unused pair of electrons; make conj. acid
- The base need to provide both e- as protons has no e-

If a compound has a pair of e- but can’t donate them then it is not base

Question 4

Neutral

Answer 4

A compound that is not an acid or a base

Question 5

Lewis acids

Answer 5

electron pair acceptors

Question 6

Lewis base

Answer 6

Electron pair donor

Question 7

HA

Answer 7

HA represent any acid
- HA =Ka=> H (+) + A(-)

Ka= [H+][A-]/[HA]
- For strong acids Ka will be large (too large in fact) = pKa will be small (carboxylic acid got a pKa of 4-5)
- pKa = -logKa = -log (10^-4)=4

Question 8

Strongest acid in water

Answer 8

H3O+ with a pKa = 0

Question 9

Strongest base in water

Answer 9

HO- with a pKa of 14

Question 10

Delta G

Answer 10

Delta G = -RT logKa
- R is gase constant (1.987 cal/mol)
- T is temperature in K

It is the basically the E of product - E of the starting material
- It is diretly proportional to the pKa of the acid as
– pKa = Detal G/RT

Question 11

acid/base and product relationship

Answer 11

The more stabilized the Conj. Base (product) => The stronger the acid (lower pKa)
- EWG also stabilize developing (-) charge and increase acidity
The more stabilized the Conj. Acid (product) => the stronger the base (higher pKa)

Question 12

Acetic Acid (CH3) Vs. Trufluoroacetic acid (CF3)

Answer 12

CH3 CO2H => CH3CO2(-) + H(+)
- CH3 is e- donating and it result into a less stable as the e- is attracted to the( -)
- pKa = 4.8

CF3CO2H => CF3CO2(-) + H(+)
- CF3 is most e- withdrawing => the (-) charge is attacted and can be delocalized +> more stable
- pKa = -0.3

EWG stabilize (-) and makes the pKa lower

Question 13

Kb

Answer 13

Kb is the base association constant
Kb=[BH+]/[B-][H+]

Kb will be large for strong bases => pKb will have small values
- OH- is the strongest base in water
– The one which donate it’s e- pair most readily

Question 14

pKa and pKb relationship

Answer 14

pKa (acid) + pKb (Conj. Base) = 14
pKb (base) + pKa (Conj. Acid) = 14
- This mean if you have pKa or pKb you just need to substract it from 14 to get the pK you missing

Question 15

Amines Vs. Alcohols and Ether

Answer 15

Amines (pKb = 5) (2>3>1 with ammonia as least basic) is is much stronger base compared to alcohols and ether (pKb = 14)
- O is more electronegative (3.5) than nitrogen (3.0) and holds onto it’s lone pair tighter
– when e- are not shared readily then they are less likely to form bonds with protons (weaker base)

Water (H2O) is a very weak base and very weak acid
- it hase both acidic and basic proterties which is called amphoteric

Question 16

Hydroxide anion (OH-)

Answer 16

It’s a conjugated baase of water that is a strong base
- The presence of a third pair of e- on a small atoms => repulsion occuring => use of the extra e- to make new bonds

The weaker the acid => the stronger it’s conj. base
The weaker the base => the stronger it’s conj. acid

Question 17

Compounds with more than one acidic sites

Answer 17

The stronger acid will be the first one to donate it’s proton

Question 18

Compounds with more than one basic sites

Answer 18

The stonger base will be the first to accept a proton

Question 19

Salts

Answer 19

When acid react with a base it produce salt
- If a benzoic acid react with sodium hydoxide => sodium benzoate (salt)
- If pyridine react with hydrochloric acid => pyridinium chloride (salt)

Majority of drugs are sold as salts because they are charged
- This mean they have good water solubility
- Usually crystalline; easier to handle

Question 20

Henderson Hasselbalch Equation

Answer 20

pKa = pH - log(-A/HA) or + log (HA/A-)
All one to find % of acid that will exist in ionized form at any given pH
- % ionized = 100[ionized]/([ionized]+[nonionized])

Ex. AcOH (pKa=4.8) => H(+) + AcO(-)
What % of acetic acid is ionized at pH 5.8
1) 4.8=5.8+log([AcOH]/[AcO-])
2) -1=log ([AcOH]/[AcO-])
3) 1/10=[AcOH]/[AcO-]
4) % ionized = 10/(1+10) = 90.9%

Question 21

Bronsted Lowry over Lewis

Answer 21

• Got big effect on how molecule behave in biological environment
• Neutral molecules => protonated => (+) charge => more H2O soluble

Question 22

Ionization

Answer 22

For positively charged acids, the acid form is ionized and it’s Conj. base is unionized

NH4(+)=> NH3 + H(+)

pKa=pH+log[NH4(+)/[NH3]
- 9.2(NH3 pKa)= 7.4+log[NH4(+)/[NH3]
–1.8=log[NH4(+)/[NH3]
— 1584893/100000000=[NH4(+)]/[NH3]
—-100000000/(1584893+100000000)=98.4%

Question 23

pKa and pH

Answer 23

pKa is a property of a compound (or a group within a compound)
pH is a property of the medium (solvent)
- Stomach: pH of 1
- Intestine (duodenum): pH of 5
- Intestine (lower ileum): pH of 8
- Circulating fluids (plasma,..): pH of 7.4

Question 24

Acidic/Basic strength is determined by?

Answer 24

The availability of e- to form and maintain a bond with H+
- If e-density is DONATED to the bond w/H+, then the compound is better able to form/maintain said bond=> pka increase, pKb decrease
– Compounds like these are stronger bases and weaker acid
- If e density is withdrawn from the bond w/H+, the compound is less able to form/maintain said bond => pKa decrease, pKb increase
– Compounds like these are weaker bases and stronger acids

Question 25

EWG

Answer 25

Increase acidity = Increase pKb = decrease pKa
Decrased basicity = Increase pKb = decrease pKa
- Stabilize the (-) charge left after H+ leaves by accepting exess e- density
- Destabilize the (+) charge of H+ gain

Question 26

EDG

Answer 26

Increased basicity = increase pKa = decrease pKb
Decreased acidity = Increase pKa = decrease pKb
- Stabilize the (+) charge of H+ gained by donaiting excess e- density
- Destabilize the (-) charge after H+ leaves

Question 27

Factors that affect e- availability

Answer 27

Induction
Resonance
Hybridisation

Question 28

Induction

Answer 28

e- density is affected (attracted) by the electronegative atoms
- The more electronegative the heteroatom, the stronger the induction attaction
- High e- density can repel other e- and act as EDGs
- Induction decrease rapidly as distance increase

Question 29

Resonance

Answer 29

e- in conjugated system (spread excess e- density over a larger area) favor resonance and disfavor bonds w/H+
- Distance doesn’t affect it

Amides need resonance to stabilize
- don’t have e- to bond w/H+ so it moves the pi-bond

Phenol: Stabilized by conjugation w/benzene ring
- Adding NO2 (strong EWG) greatly increase acidity (decrease pKa)

Carboxylate ion is stabilized by resonance

Amidine is stabilized by resonance
- guanidine is the strongest basic FG because of abundant resonance

Question 30

Hybridization

Answer 30

Greater the S character (s/p) = smaller orbitals => e- held closer to nucleus => e- being less abailable to bond w/H+
- This mean the higher the S character => lower pKa

Amines:
- 3° amines (N bonded with three atoms):sp3 (pKa 9-11)
- amines in aromatic ring: sp2 (pKa 5)
- Nitriles (N triple bond C): sp1 (pKa 0)

Question 31

Amines pKa

Answer 31

Range from 9-11
- 2° amines are strongest bases because of substituet effect
- 3° amine are strong for the same reason but the hindrance affect basicity
- 1° amines do not have substituent to shagre the + charge with so

2° > 3° > 1°

Question 32

Thiols and alcohols

Answer 32

Thiols are stronger acids thatn alcohol because S is larger than O
- Allow it to spread the (-) charge over a greater area
- Induction DOES NOT outweight resonance

Phenols < Thiols < alcohols

Imidazole is e- rich while py is e- deficient