Acid and Bases Flashcards
What type of environment in which drugs exert their biological activity
Aqueous
Acid
Bronsted and Lowry
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
Base
Bronsted and Lowry
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
Neutral
A compound that is not an acid or a base
Lewis acids
electron pair acceptors
Lewis base
Electron pair donor
HA
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
Strongest acid in water
H3O+ with a pKa = 0
Strongest base in water
HO- with a pKa of 14
Delta G
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
acid/base and product relationship
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)
Acetic Acid (CH3) Vs. Trufluoroacetic acid (CF3)
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
Kb
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
pKa and pKb relationship
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
Amines Vs. Alcohols and Ether
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
Hydroxide anion (OH-)
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
Compounds with more than one acidic sites
The stronger acid will be the first one to donate it’s proton
Compounds with more than one basic sites
The stonger base will be the first to accept a proton
Salts
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
Henderson Hasselbalch Equation
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%
Bronsted Lowry over Lewis
- Got big effect on how molecule behave in biological environment
- Neutral molecules => protonated => (+) charge => more H2O soluble
Ionization
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%
pKa and pH
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
Acidic/Basic strength is determined by?
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
EWG
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
EDG
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
Factors that affect e- availability
Induction
Resonance
Hybridisation
Induction
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
Resonance
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
Hybridization
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)
Amines pKa
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°
Thiols and alcohols
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
