Therapeutics I Michael B.

Bolger 1/5/00

Physicochemical Properties of Drugs
Objectives: At the end of the next hour: 1. The student should be able to calculate the degree of ionization for an acidic or basic drug using an approximate method of calculation that does not require the use of calculators or computers. Example: (Acetic Acid, pKa ~5)

O R OH R

O R

O O

O Ionized species is stabilized by resonance.

If pKa ~5 then acetic acid will be 50% ionized at pH~5. When the pH is lowered by one pH unit, the hydrogen ion concentration is increased by 10 fold resulting in a shift of equilibrium toward the unionized species. The shift follows the laws of mass action and results in ~90% unionized at pH~4. To calculate an approximate the degree of ionization just subtract the pka from the pH, round off to the nearest integer to determine how many 9s to use. Next determine which is the major species, and write down that many nines with a decimal point after the second nine. For example to determine the degree of ionization of acetic acid in the stomach at pH~1: pKa - pH = 4, therefore acetic acid is 99.99% unionized in the stomach. 2. The student should know the approximate pKa values for the following chemicals which illustrate most of the important concepts of acid-base chemistry (inductive electron withdrawing, resonance, and loss of aromaticity) in drugs: Compound acetic acid (sp2) ethanol (sp3) methylamine (sp3) ethylamine (sp3) pyridine (sp2) pyrole (sp2) -> (sp3) pyrolidine (sp3)
*

pKa ~5 ~15 ~10* ~10* ~5* ~0* ~10*

Compound trifluoroacetic A. phenol (sp2) aniline (sp2) acetamide (sp2) pyrimidine (sp2) imidazole (sp2) benzoic acid (sp2)

pKa ~0 ~10 ~5* ~0* ~0* 7*,13 ~4

Comparison Principle Inductive e- withdraw Resonance e- withdraw Resonance e- withdraw Resonance e- withdraw Inductive e- withdraw Loss of aromaticity

3.

These are the pKa’s of the conjugate acid of the base. The student should be able to rank the following functional groups on the basis of their lipophilic (π), electronic (s), and steric (MR) properties:

97 -0.53 1.94 6.65 6.71 -0.13 0.80 -0.Physicochemical Parameters By Type Subst. Group MR 5.66 0.23 -0.96 14.94 14.12 0.06 0.36 2.03 8.00 0.87 8.97 1.57 -0.02 0.02 -0.93 14.94 5.86 0.86 1.18 0.71 0.54 0.00 0.96 14.85 5.18 13.37 0.65 10.23 0.37 0.00 0.42 5.87 5.87 1.88 11.03 0.00 -0.57 σpara 0.03 0.15 -0.53 -0.50 0.50 0.55 -0.23 0.14 1.06 0.30 14.00 0.18 0.97 -0.13 MR 5.88 10.88 -0.27 0.78 -0.93 1.78 -0.86 -0.71 0.54 -0.36 -F -H -OH -CF3 -NH2 -CH3 -Cl -CN -NO2 -OCH3 -Br -CH2CH3 -COCH3 -I -NHCOCH3 -C(CH3)2 -CH2CH2CH3 π -1.88 13.56 1.15 -0.12 1.14 0.66 0.96 7.55 -0.53 1.67 -0.55 0.30 13.18 14.12 -0.56 0.02 1.03 8.17 0.54 -0.65 10.88 -0.42 0.02 1.88 5.92 5.54 -0.66 0.55 σpara -0.57 -0.80 -0.80 -0.33 -NH2 -NHCOCH3 -NO2 -OH -CN -COCH3 -OCH3 -H -F -CH3 -Cl -Br -CF3 -CH2CH3 -I -C(CH3)2 -CH2CH2CH3 π -1.00 -0.66 0.23 -0.50 0.06 -0.53 1.23 0.17 -0.17 0.00 0.00 0.33 11.02 2.03 5.50 -0.00 0.57 -0.13 -0.00 -0.88 -1.66 -0.06 0.71 0.23 -0.87 5.80 σpara -0.15 -0.02 0.96 By Electronic Subst.92 1.36 6.23 0.37 -0.03 8.02 10.65 6.33 7.42 2.33 7.86 1.93 7.12 0.18 7.67 -0.67 0.97 0. Group MR 1.23 0.14 0.66 -0.18 -0.93 7.15 0.96 .56 0.85 11.23 0.66 Subst.37 0.67 -0.66 0.13 MR 0.23 0.03 2.03 6.56 1.00 0.02 -1.02 0.96 14.55 -0.02 6. Group -NH2 -OH -OCH3 -CH3 -CH2CH3 -C(CH3)2 -CH2CH2CH3 -NHCOCH3 -H -F -I -Cl -Br -COCH3 -CF3 -CN -NO2 By Size Subst.85 7. Group -H -CH3 -CH2CH3 -CH2CH2CH3 -C(CH3)2 -OCH3 -NH2 -F -Cl -Br -I -CF3 -OH -COCH3 -NHCOCH3 -NO2 -CN By Lipophilicity π 0.02 1.55 1.92 13.27 -0.02 5.30 14.36 7.15 -0.17 -0.92 6.30 11.88 1.23 0.96 14.55 1.00 -0.94 14.14 0.78 0.78 π 0.55 σpara 0.23 0.27 -0.15 0.18 5.96 14.15 -0.15 -0.18 0.85 6.27 0.42 14.

This is because protonation of pyrole requires that 2 electrons be removed from the π-system which destroys aromaticity .4 N H N pKa=15 pKa=-1 charged in stomach at pH 1.6 + NH + pka 10 5 Aromaticity greatly effects the acid-base properties of heterocycles: Uncharged in blood At pH = 7.5 Phenol R NH3 10 Aniline 0. H + N pKa=5 H N + H N The pyrole ring would be neutral in any biological system.Review of Acid-Base Properties: Acid or Carboxylic Acid Conjugate Acid O Amine Amide + R NH3 + O R O N H H R OH pka Acid or Conjugate Acid 4.0 Protonation of pyridine does not effect aromaticity.3 and 16 Pyridine OH NH3 4.

H N H N + H H N N pKa = 10 Pyrolidine acts like a normal tertiary amine Indole would also remain neutral in a bio-system N pKa=8.Pyrimidine would always be neutral in a bio-system N N H N pKa=13 N N + However. the lone pair electrons are available for H-bonds as in DNA. Thus.9 H N N pKa=2. the pKa is more basic than pyrole.3 H N N H N N Imidazole retains aromaticity when protonated. H + N pKa=1.4 Purine is more acidic and less basic than imidazole .

2 D. C.57 σpara 0.97 -0.96 14. Use the table of physicochemical properties shown above to select a substitution at the position para to the carboxylic acid.03 5. O F F F OH F A.30 14. that will decrease lipophilicity and increase the pKa of the phenolic hydroxyl compared to the trifluoromethyl substitution.15 -0.66 0.27 -0.93 7. 4 .65 10.55 1.36 6.18 0.00 0. 0 B.13 -0. D. the phenolic hydroxy group is 99% unionized and the carboxylic acid is 50% ionized.85 11.33 4.42 0.80 -0. What is the pKa of the carboxylic acid? A. Group -H -CH3 -CH2CH3 -CH2CH2CH3 -C(CH3)2 -OCH3 -NH2 -F -Cl π 0. Group -Br -I -CF3 -OH -COCH3 -NHCOCH3 -NO2 -CN π 0. sticks too tightly to a plasma carrier protein and does not penetrate to its cellular receptor. Your lead structure (a weak acid).53 -0.00 -0.15 -0. You are a chemist working at King Konglomerate in New Jersey.78 0.67 -0.17 -0.50 0. ethyl (-CH2CH3) cyano (-CN) methoxy (-OCH3) iodo (-I) nitro (-NO2) OH F Assume that the pKa of the phenolic hydroxyl group in the parent molecule is 4.96 7.56 1.71 σpara 0.92 6.23 0.94 5.23 MR 1.86 1.66 MR 8.00 0. B. E. 5.02 -1.14 0.87 5.12 0.54 -0.88 13.03 Subst. At the current pH.02 2.88 -0. 3 E.02 1. shown below.06 0.Subst. 1 C.55 -0.23 0.18 14.37 0.

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