18 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY The chromatographic methods suffer the disadvantage that the retention time is lin early related to the partition coefficient,i.e.for a doubling of the LogP,there is a tenfold increase in the retention.This often requires different length columns to be used,short ones for high LogP values and long ones for low values. Relationships between Log P and activity The partition coefficient is also a ver useful parameter that may be ased in combination with the pKa predict the distributior of a dru ound in a biol such as absorption,excretion and penetration into the CNS may be related to the Log P value of a drug.Drugs should be des ned with the lowest possible Log P,to reduce toxicity,non specific binding,increase ease of formulation and bioavailability. Relationships between LogP and activit e often found in stru 1 、H leads value for the log pf a desired activity o selectiv e distribution.Relatio of the ypes are generated using egression ctivity with measured partition coefficients. Activity m log p-clog p)2-k(parabolic) Activity=m log P-c(blog P+1)-k(rectilinear)(where m,k and c are co The best way of relating LogP,pKa and other physico-chemical properties to biologica activity is using multivariate techniques such as Principal Components Analysis and Partia Least Squares regression DISSOCIATION CONSTANTS The dissociation constant is one of the most important characteristics of a pharmaceutical compound.Majority of drugs are weak acids or weak bases and like acetic acid or ammonia. ater to form conjugate pairs.The pKa or Dissociation constant'is a measure an acid or a base and is sometin s called the acic uty const nt or the ioni tion constar a nume stance,or t of that on as the equilibrium constant. Weak acid drug Water H2O*+Weak base drug anion- acid base conjugate acid conjugate base Weak base drug+Water OH- HWeak base drug Let us consider equation for the protolysis of water by an acidic drug (HA). HA+HO H0+A At equilibrium,the velocity of the reaction proceeding to the ionized components(k)is equal to the velocity of the reaction resulting in the unionized HA and HO()
18 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE3-1.PM5 The chromatographic methods suffer the disadvantage that the retention time is linearly related to the partition coefficient, i.e. for a doubling of the LogP, there is a tenfold increase in the retention. This often requires different length columns to be used, short ones for high LogP values and long ones for low values. Relationships between Log P and activity The partition coefficient is also a very useful parameter that may be used in combination with the pKa to predict the distribution of a drug compound in a biological system. Factors such as absorption, excretion and penetration into the CNS may be related to the Log P value of a drug. Drugs should be designed with the lowest possible Log P, to reduce toxicity, nonspecific binding, increase ease of formulation and bioavailability. Relationships between Log P and activity are often found in series where structural modifications have not significantly affected the pKa values. Hansch in 1964 showed that these relationships were often parabolic hence the relationship often leads to an optimum value for the log P for a desired activity or selective distribution. Relationships of the following types are generated using regression analysis to correlate observed biological activity with measured partition coefficients. Activity = m log P + k′ (linear) Activity = m log P – c(log P)2 – k(parabolic) Activity = m log P – c(blog P +1) – k(rectilinear) (where m, k and c are constants) The best way of relating LogP, pKa and other physico-chemical properties to biological activity is using multivariate techniques such as Principal Components Analysis and Partial Least Squares regression. The dissociation constant is one of the most important characteristics of a pharmaceutical compound. Majority of drugs are weak acids or weak bases and like acetic acid or ammonia, they react with water to form conjugate pairs. The pKa or ‘Dissociation constant’ is a measure of the strength of an acid or a base and is sometimes called the acidity constant or the ionization constant. It is a numerical representative of the relative proton transfer for that substance, or the likelihood of that compound donating a proton. It is calculated in the same fashion as the equilibrium constant. Weak acid drug + Water H3O+ + Weak base drug anion– acid base conjugate acid conjugate base Weak base drug + Water OH– + H+ Weak base drug base acid conjugate base conjugate acid Let us consider equation for the protolysis of water by an acidic drug (HA). HA + H2O H3O+ + A– At equilibrium, the velocity of the reaction proceeding to the ionized components (k1) is equal to the velocity of the reaction resulting in the unionized HA and H2O (k2)
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 19 (l )[HA][H2O] (k。)=HO+1[A the case,the ter in the above equation may be ield K=2(55.53k1=AH,0*VHA where 55.53 is the number of moles of water per liter at 25C. tion,and spectr ophotometric data may be used to deter ng point mine eSaocationco stant. Ex:Acetaminophen is an acidic drug with aK of1 s mu ch I in aqueous solution than aspirin (acetyl salicylic acid).whi toion Often it is cumbersome to deal with exponential forms,so pK may be used to describe the tendency of a weak acid to ionize.The following equation should be used to calculate the pk of a substance. pK =-log [IA-I[H O"V/IHA]l Relationship to pK and acid strength:For almost all the drugs,the dissociation he rug is a w 10 s to 01 to giv 01 the ac. va the reh of th 0g9 the d ac of the base)te at the (the value)the ginal bas In pcid of a base attracts the oton more than a weak base does. Some examples of acidic and basic drugs; Acidic Drugs: HA +H,O HO+A- K P pK Penicillin V 2.0×10-3 5.4×10-12 2.7 11.3 Acetylsalicylic Acid 3.3×10- 3.1×10-11 36 10.5 Ascorbic Acid 5.0×10- 2.0×10-10 9.7 Zidovudine 2.0×10-10 5.0×105 9.7 4.3 Basic Drugs A+H20 HA*+-OH K K Caffeine 2.5×10 4.0×10- Zalcitabine 6.3×100 1.6×10-10 4.2 9.8 Theophylline 3.4×109 1.6×10-9 5.2 8.8
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 19 C-8—N-CHEMI\CHE3-1.PM5 (k1) = [HA][H2O] (k2) = [H3O+][A–] Weakly acidic and basic drugs ionize only slightly in the presence of water. That being the case, the concentration of water in the above equation may be taken as a constant, by rearranging the equation to yield: Ka = k2 (55.53)/k1 = [A–][H3O+]/[HA] where 55.53 is the number of moles of water per liter at 25°C. This value, Ka, gives us numeric value to express the degree to which a compound ionizes, or dissociates, in aqueous solution. Dissociation constants are determined by experimental data, and are unique to each molecule. Conductivity, freezing point depression, pH of solution, and spectrophotometric data may be used to determine a compound’s dissociation constant. Ex: Acetaminophen is an acidic drug with a Ka of 1.2 × 10–10, and is thus much less likely to ionize in aqueous solution than aspirin (acetyl salicylic acid), which has a ka of 3.27 × 10–4. Often it is cumbersome to deal with exponential forms, so pKa may be used to describe the tendency of a weak acid to ionize. The following equation should be used to calculate the pka of a substance. pKa = – log [[A–][H3O+]/[HA]] Relationship to pKa and acid strength: For almost all the drugs, the dissociation constants are reported as pKa, regardless of whether the drug is a weak acid or a weak base. For acids, Ka refers to the ability of the acid to give out the proton. Therefore, the higher the tendency of an acid to give out the proton, the stronger is the acid (or the lower the pKa value). For bases, Ka refers to the ability of the conjugated acid form of the base to give out the proton. Therefore, the higher the conjugated acid’s (of the base) tendency to give out the proton (the lower the pKa value), the weaker the original base. In other words, the conjugated acid of a stronger base has a lesser tendency to give out the proton because a strong base attracts the proton more than a weak base does. Some examples of acidic and basic drugs; Acidic Drugs : HA + H2O H3O+ + A– Ka Kb pKa pKb Penicillin V 2.0 × 10–3 5.4 × 10–12 2.7 11.3 Acetylsalicylic Acid 3.3 × 10–4 3.1 × 10–11 3.5 10.5 Ascorbic Acid 5.0 × 10–5 2.0 × 10–10 4.3 9.7 Zidovudine 2.0 × 10–10 5.0 × 10–5 9.7 4.3 Basic Drugs : A + H2O HA+ + –OH Ka Kb pKa pKb Caffeine 2.5 × 10–4 4.0 × 10–11 3.6 10.4 Zalcitabine 6.3 × 10–5 1.6 × 10–10 4.2 9.8 Theophylline 3.4 × 10–6 1.6 × 10–9 5.2 8.8
20 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY Morphine 74×10-7 7.4×10-7 7.9 61 Erythromycin 2.0×10-9 6.3×10-6 8.8 5.2 ionized a ratio of i ortion of drug molecules in the ns The and othe affec dr g's solubilit stics..The pK。allo rmin e the h pKa nd L rug n HYDROGEN BONDING The hydrogen bond is a special type of dipole-dipole interaction between the hydrogen atom in a polar bond such as N-H,O-H,or F-H and an electronegative atom O,N,or F atom.This interaction is written as A-H........B. sent O,Nor F.A-H is one molecule (or) of anothe part of a molecule and B is a par and the nts th AHB can deviate as much as 30 from linearity onding in and HF H H0…H0 H-N…H0 …H-f H 可 H H20-H,0 NH,-H2O NH,-HF Generally the hydrogen bonding is classified into2types (A)Intermolecular hydrogen bonding (B)Intramolecular hydrogen bonding (A)Interr nolecular hydrogen hydrog bon g occurs be an two mo cules of same compour and results in the formation o H H H H 44…H …NH H0…H0…H0 H H H H Hydrogen bonding in ammonia Hydrogen bonding in water Intermolecular hydrogen bonding increases the boiling point of the compound and also its solubility in water.The molecules that are able to develop intermolecular hydrogen bond- ing improve their solubility by the formation of intermolecular hydrogen bonding with water. Ex:Ethanol shows higher boiling point and higher solubility in water than dimethyl ether even though both have the same molecular weight
20 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE3-1.PM5 Morphine 7.4 × 10–7 7.4 × 10–7 7.9 6.1 Erythromycin 2.0 × 10–9 6.3 × 10–6 8.8 5.2 Importance of pKa. It is because pKa affects the proportion of drug molecules in the ionized and unionized forms. The ratio of ionized over unionized form affects drug’s solubility, permeability, binding, and other characteristics. The pKa allows to determine the charge on a molecule at any given pH. pKa and Log P measurements are useful parameters in understanding the behavior of drug molecules. The hydrogen bond is a special type of dipole-dipole interaction between the hydrogen atom in a polar bond such as N—H, O—H, or F—H and an electronegative atom O, N, or F atom. This interaction is written as A—H ·············B. A and B represent O, N or F. A—H is one molecule (or) part of a molecule and B is a part of another molecule; and the dotted line represents the hydrogen bond. These three atoms usually lie along a straight line, but the angle AHB can deviate as much as 30° from linearity. Ex: Hydrogen bonding in NH3, H2O and HF H—O ············· H—O H H O—H O 2 2 H H—N ············· H—O H H NH —H O 3 2 H H—N ············· H—F H H NH —HF 3 Generally the hydrogen bonding is classified into 2 types (A) Intermolecular hydrogen bonding (B) Intramolecular hydrogen bonding (A) Intermolecular hydrogen bonding. In this type, hydrogen bonding occurs between two or more than two molecules of the same compound and results in the formation of polymeric aggregate. H—N ············· H—N ············· N—H H HH H HH Hydrogen bonding in ammonia H—O ············· H—O ············· H—O HHH Hydrogen bonding in water Intermolecular hydrogen bonding increases the boiling point of the compound and also its solubility in water. The molecules that are able to develop intermolecular hydrogen bonding improve their solubility by the formation of intermolecular hydrogen bonding with water. Ex: Ethanol shows higher boiling point and higher solubility in water than dimethyl ether even though both have the same molecular weight.
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 21 Molecular Weight Boiling Point Ethanol (C,H2O) 46 78°C Dimethyl ether (C.HO) -25C Diethyl ether (CHO) 14 61°C 1-Butanol(C HO) 74 118℃ n e en chelation and frequently occurs in organic compounds.Sometimes intramolecular hydrogen bonding develops a six or 5-membered ring.Ex: H N=0 0 Hydrogen bonding in Hydrogen bonding in Hydrogen bonding in o-chlorophenol o-nitro phenol 2,6 dihydroxy benzoic acid tuted groups restricts the possibility of inte nolecular hydrogen bonding with wate and thus of the molecules which would have raised the melting point,boiling point. Compound Boiling Point o-Nitrophenol N=0 215C hydrogen bonding in o-nitro phenol p-Nitrophenol OH 279℃ NO
PHYSICO-CHEMICAL PROPERTIES OF ORGANIC MEDICINAL AGENTS 21 C-8—N-CHEMI\CHE3-1.PM5 Molecular Weight Boiling Point Ethanol (C2H6O) 46 78°C Dimethyl ether (C2H6O) 46 – 25°C Diethyl ether (C4H10O) 74 61°C 1-Butanol (C4H10O) 74 118°C (B) Intramolecular hydrogen bonding. In this type, hydrogen bonding occurs with in two atoms of the same molecule. This type of hydrogen bonding is commonly known as chelation and frequently occurs in organic compounds. Sometimes intramolecular hydrogen bonding develops a six or 5-membered ring. Ex: O H Cl O O H N=O O O C H H O O H Hydrogen bonding in o-chlorophenol Hydrogen bonding in o-nitro phenol Hydrogen bonding in 2, 6 dihydroxy benzoic acid Intramolecular hydrogen bonding decreases the boiling point of the compound and also its solubility in water. This is because of the fact that the chelation between the ortho substituted groups restricts the possibility of intermolecular hydrogen bonding with water and thus prevents association of the molecules, which would have raised the melting point, boiling point. Compound Boiling Point O O H N=O Intra molecular hydrogen bonding in o-nitro phenol o-Nitrophenol 215°C OH NO2 p-Nitrophenol Intermolecular hydrogen bonding 279°C
22 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY m-Nitrophenol OH 279℃ NO Effects of hydrogen bonding.Almost all physical properties are affected by hydro gen bonding.Here only those properties that are prominently altered such as boiling points melting point,water solubility etc.,are discussed.In addition to physical properties severa affected by ydrogen bondingaracter basie character.properesr carony group are aso (i)Boiling and melting points.Intermolecular hydrogen bonding increases the boiling point of the compound due to association of several molecules of the same compound.As a result the intermolecular forces are increased and hence more energy (large amount of heat)is required to dissociate the molecules for vaporization.Intramolecular hydrogen bonding decreases the boiling point of the compound because of the fact that the chelation between the groups of same mo restrcts the possibinty of intermole lar hydrogen bonding and thus prevents association of the molecules,which would nave raised the melting point and bolling (ii)Water solubility.Solubility of a substance increases tremendously when hydroger bonding is possible between the solvent and the solute.Ex:Methanol and ethanol are highly soluble in water due to hydrogen bonding between molecules. R-0…H-0…H-0 rs may be attributed to the fact that these compounds make ava H groups for hydrogen bonding (iii)Strength of acids.Any structural feature that contributes for the greater stability of anion in comparison to free acid will shift the ionization equilibrium to the right.Thus if the anion of acid were stabilized due to intramolecular hydrogen bonding,there would be marked increase in the strength of acid.Ex:The ionization constant of salicylic acid is higher than the other two isomers and is 17 times more acidic than benzoic acid. (iv)Spectroscopic properties.The hydrogen bonding shifts the position of bands in infrared and NMR spectra of organic compounds.Ex:Infrared spectrum of ethyl alcohol in vapour phase shows absorption band at 3700 cm-due to free hydroxyl group.In solution this band is completely replaced by a broad band around 3500 cm-which is characteristic of hy- drogen bonded hydroxyl groups. (v)Surface tension and Viscosity.The compounds which possess hydrogen bonding are found to have higher surface tension and viscosity.Glycerol,glycol,sulphuric acid,sugar syrup,phosphoric acid,etc.,are viscous liquids due to extensive hydrogen bonding between their molecule.Due to more number of hydroxyl(-OH)groups,the extent of hydrogen bond- ing is more in glycerol.So,it is more viscous than glycol
22 PRINCIPLES OF ORGANIC MEDICINAL CHEMISTRY C-8—N-CHEMI\CHE3-1.PM5 OH NO2 m-Nitrophenol 279°C Effects of hydrogen bonding. Almost all physical properties are affected by hydrogen bonding. Here only those properties that are prominently altered such as boiling points, melting point, water solubility etc., are discussed. In addition to physical properties several chemical properties like acid character, basic character, properties of carbonyl group are also affected by hydrogen bonding. (i) Boiling and melting points. Intermolecular hydrogen bonding increases the boiling point of the compound due to association of several molecules of the same compound. As a result the intermolecular forces are increased and hence more energy (large amount of heat) is required to dissociate the molecules for vaporization. Intramolecular hydrogen bonding decreases the boiling point of the compound because of the fact that the chelation between the groups of same molecule restricts the possibility of intermolecular hydrogen bonding and thus prevents association of the molecules, which would have raised the melting point and boiling point. (ii) Water solubility. Solubility of a substance increases tremendously when hydrogen bonding is possible between the solvent and the solute. Ex: Methanol and ethanol are highly soluble in water due to hydrogen bonding between molecules. R—O ············· H—O ············· H—O HRR The high solubility of polyhydric phenols and sugars may be attributed to the fact that these compounds make available greater number of —OH groups for hydrogen bonding. (iii) Strength of acids. Any structural feature that contributes for the greater stability of anion in comparison to free acid will shift the ionization equilibrium to the right. Thus if the anion of acid were stabilized due to intramolecular hydrogen bonding, there would be marked increase in the strength of acid. Ex: The ionization constant of salicylic acid is higher than the other two isomers and is 17 times more acidic than benzoic acid. (iv) Spectroscopic properties. The hydrogen bonding shifts the position of bands in infrared and NMR spectra of organic compounds. Ex: Infrared spectrum of ethyl alcohol in vapour phase shows absorption band at 3700 cm–1 due to free hydroxyl group. In solution this band is completely replaced by a broad band around 3500 cm–1 which is characteristic of hydrogen bonded hydroxyl groups. (v) Surface tension and Viscosity. The compounds which possess hydrogen bonding are found to have higher surface tension and viscosity. Glycerol, glycol, sulphuric acid, sugar syrup, phosphoric acid, etc., are viscous liquids due to extensive hydrogen bonding between their molecule. Due to more number of hydroxyl (—OH) groups, the extent of hydrogen bonding is more in glycerol. So, it is more viscous than glycol