ACID and BASES - a Summary

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1 AID and BASES - a Summary Stefan Svensson 2004 Brönsted-Lowry : Acids donate protons Lewis -acid : Electron pair acceptor Bases accept protons Lewis-base: Electron pair donator. Acetic acid ättiksyra Aniline Acidity constant Ka: K eq = [ 3 + ] [ 3 - ] [ 3 ][ 2 ] K a = K eq [ 2 ] = [ 3 + ] [ 3 - ] [ 3 ] = 1,76 x 10-5 pk a = -log K a =4,76 Ju starkare syra - ju svagare korresponderande bas. Basstyrkan kan relateras till pka för dess korresponderande syra. Ju större pka värde för korresponderande syra- ju starkare är basen. Relative strength for some acids and their conjugate bases, AID pka onj. BASE Strongest acid SbF 6 > -12 SbF 6 - Weakest base l - 7 l ,7 - ( 3 )3 18 ( 3 ) Weakest acid Strongest base Ex Lewis acids: BF 3 All 3 Til 4 Znl 2 l, 3, l 4 are complete ionised in water and appears to have the same strength (the leveling effect of water)

syra - ju svagare korresponderande bas. Basstyrkan kan relateras till pka för dess korresponderande syra. Ju större pka värde för korresponderande syra- ju starkare är basen.

2 Factors that influence the acidity of an organic compound -A A The strength of the -A bond B The electronegativity of A Factors stabilising A- compared with -A D The nature of the solvent Examples 3 pka 43 3 pka 16 pka 10 R pka 4-5 A- Bonding strength to the proton -F < -l < -Br < -I Increased acidity pka: 3, decreased bonding strength F - > l - > Br - > I - Increased Basicity 2 < 2 S < 2 Se igher acidity - > S - > Se - Increased Basicity B- Acidity increase with electronegativity 4 < 3 < R- < F Electronegativity affect both polarity and the stability of the anion. Acidity increase with increased s-character in the hybridisation 3-3 < 2=2 < Increased acidity sp3 sp2 sp pka: Increased s-character binds the electrons closer to the carbon nucleus More s-contribution lower energy and higher anion stability Ex pk a = 25 pk a = 33

2 Se igher acidity - > S - > Se - Increased Basicity B- Acidity increase with electronegativity 4 < 3 < R- < F Electronegativity affect both polarity and the stability of the anion.

3 Lower pka for arboxylic acids than Phenols due to: Resonance structures of the anion have identical energy The anion contain two electronegative oxygen atoms pka 3,8 Phenol: pka 10 pk a ,9 l 2 3 l 2 4,8 2,9 The negative charge is spread by electronwithdrawing and thereby stabilising the anion D. Polar solvent with high dielectric constant (ε) have better ability to solvate ions Water is extremely effective as ion solvating medium and is readily polarised, and can thereby stabilise and solvate both cations and anions The solvent must act as a base otherwise can not acids dissociate. Ex. l is a strong acid in methanol but not in toluene.

Polar solvent with high dielectric constant (ε) have better ability to solvate ions Water is extremely effective as ion solvating medium and is readily polarised,

4 AIDS Aliphatic acids Alkyl groups can inductively decrease the acid strength ompare: acetic acid and formic acid pka 4,76 versus 3,77 But often depends differences in relative solvation possibilities of ionisation. G o = o - Τ S o and G o = RT log K eq pka G o o Τ S o Acetic acid Formic acid 4,76 6,5-0,13-6,6 Kcal 3,77 5,1-0,07-5,17 Kcal Low enthalpy The energy required for dissociation of the - bond is canceled by the energy evolved in solvating the resultant ions. Entropy has a greater effect Through solvation of the ions by water molecules is the orderliness increased. Differential solvation of the acid anions makes the acid strength to differ. Formiat ion is stronger solvated. For other short aliphatic acid (3-5) are the differences in pka small, Minor steric effects may count for the differences (pka ,05) ybridisation 3 2 pka 4,88 sp 3 2 4,25 sp 2 1,88 sp Stronger acid Electrons are drawn closer to unsaturated carbon nucleus - larger s contribution This change the inductive effect from donating to withdrawing when sp 3 sp. Similar to acidities in the serie: ethane - ethene- ethyne

303 RT log K eq pka G o o Τ S o Acetic acid Formic acid 4,76 6,5-0,13-6,6 Kcal 3,77 5,1-0,07-5,17 Kcal Low enthalpy The energy required for dissociation of the - bond is canceled by the energy

5 Substituted aliphatic acids 3 F 2 l 2 Br 2 I 2 4,76 2,57 2,86 2,90 3,16 l l l 2 l l l 2,86 1,25 0,65 Inductive effects ( electron withdrawing, EW) delocalise the negative charge over the whole of the anion. The water can be less ordered to solvate the ions. The changes in pka and then free energy is largely due to entropy factor also here. Entalphy differ only little with different substituent. The anionic charge gets more concentrated as the EW-substituent is situated further apart increased S Phenols The Inductive effect falls off with distance from orto > meta > para, but is also combined with mesomeric effect which affect primary at orto- and para-positions. 6 5 o m p ,4-( 2 ) ,4,6-( 2 ) pka 9,95 7,23 8, ,01 1,02 With more powerful EW groups the negative charge gets delocalised decreased S (solvation can be less ordered) lower pka. Alkyl groups have only marginal effects. thyl 6 5 o- 6 4 m- 6 4 p- 6 4 pk a 9,95 10,28 10,

The anionic charge gets more concentrated as the EW-substituent is situated further apart increased S Phenols The Inductive effect falls off with distance from orto > meta > para, but is also

6 Aromatic carboxylic acid Benzoic acid pka 4,20 is stronger than the saturated acid ( 4,87). Phenyl as double bond is less electron donating than saturated acids. pk a of X l Br 4,20-2,17 2,94 2,85 4,09 2,98 4,20 4,24 3,45 3,83 3,81 4,09 4,08 4,20 4,34 3,43 3,99 4,00 4,47 4,58 EW-groups increases the acid strength, mesomeric effect may also decrease strength. and - groups may have both inductive (EW) and mesomer effect (ED) depending on position. The effect can give a weaker acid also. X X rto groups may also besides short inductive distance act through space, or as few cases with intra-molecular hydrogen bonding - + Again is the S term most important for the pka value. Dicarboxylic acids The inductive EW- effect of the second falls off sharply as the -groups are separated more than one saturated carbon pk a 1,23 2,83 4,19 Maleic acid has a low pk a1 compared with fumaric acid due to intra molecular - bonding, which on the other hand also makes pka2 higher due to stabilisation. Maleic acid - - pk a1 = 1,92 pk a2 = 6,23 pk a1 = 3,02 pk a2 = 4,38 Fumaric acid For malic and succinic acid is pk a2 higher as the first - group is Elect. Donating. As the entropy has a major effect on pka:s also temperature influences the value of pka.

strength. and - groups may have both inductive (EW) and mesomer effect (ED) depending on position. The effect can give a weaker acid also.

7 BASES More convenient to use pka also for bases K a = [B] [ 3 + ] [ B + ] The smaller value of pka for B + the weaker B is as a base pk a 9,25 G o o Τ S o 12,6 12,4 0,2 Kcal Enthalpy changes are more important than entropy changes. S is low as both sides has the same kind of ions, equally solvated. Aliphatic bases Et Et 3 2 Et 2 Et Et Et pk a : 9,25 10,64 10,77 9,80 10,67 10, Alkyl groups on ammonia increases the base strengththe first one markedly, the second slightly but the third actually decrease base strength. ot only electron availability on the nitrogen also solvation of the cation must be stabilised. Tertiary amines less easily solvated. The more hydrogen atoms attached on nitrogen the more powerful solvation via - bonding between these and water. 2 R > R R > 2 2 R R R Decreasing stabilisation by solvation Increasing electron-donating inductive effect on basicity In solvent where ions are not solvated by -bonding is the order of base strength the same as the inductive effect of the alkyl groups. In chlorobensen or gas phase: But 2 < But2 < But 3

Aliphatic bases Et Et 3 2 Et 2 Et Et Et pk a : 9,25 10,64 10,77 9,80 10,67 10,93 10 88 Alkyl groups on ammonia increases the base strengththe first one markedly, the second slightly but the third

8 EW inductive groups reduce the base strength: l, 2 F3 F 3 F 3 F 3 R 2 R 2 Amide nitrogens are non basis due to mesomeric EW effect (pka 0,5). Pthalimide, with two carbonyls, is acidic and non-basic. acidic R4+ - as a ion pair has a base strength alike alkali bases Guanidine has pka of 13,6 and protonation gives three exactly equal resonance structures. Anilines pka 4,6 (ompare with cyclohexylamine pka 10,7) Unshared electrons on can interact with the delocalised π-electrons in the ring. In protonated form is this stabilisation not available. Ph 2 pka 0,8 and Ph 3 is not basic at all. Alkyl groups pka 4,62 4,38 4,84 4,67 5,15 5,10 o m p Alkyl groups do only effect little whatever position, and the main effect on the base strength is the mesomeric stabilisation of the aniline molecule with respect to the cation.

Anilines 2 2 2 2 2 2 + pka 4,6 (ompare with cyclohexylamine pka 10,7) Unshared electrons on can interact with the delocalised π-electrons in the ring.

9 Ex itro- hydroxy- and methoxy- substituted anilines o- - 0,28 m- 2,45 p- 0, ,62 o- 4,72 m- 4,17 p- 5, o- 4,49 m- 4,20 p- 5, rto position gives greatest effect due to strongest inductive effect but also by direct interaction by steric and -bonding. 3 3 Stronger base 2,4,6-trinitro-,-dimethyl aniline is much more stronger base than,-dimethylaniline or 2,4,6-trinitro-aniline, because the orto groups inhibit resonance interaction by steric reason. etrocyclic bases Pyridine (A) aromatic (sp 2 ) pka 5,2 less basic than ex. triethylamine (sp 3 ) As nitrogen becomes more multiply bonded its lone pair of electrons is accommodated in an orbital with more s character., the electron are drawn closer to the nitrogen nucleus. ompare also pka -4,3 (sp). ybridisation R 3 > > Base strength R + (A) (B) () Pyrrole (B) have aromatic character, the electron pair is incorporated in the aromatic 6 π-system, which gives a weaker base. α-arbons is more basic. Pyrrolidine () on the other hand have pka 11,3 resembling of diethylamine.

direct interaction by steric and -bonding.

Physicochemical Properties of Drugs

Therapeutics I Michael B. Bolger 1/3/02 bjectives: At the end of the next hour: Physicochemical Properties of Drugs 1. The student should be able to calculate the degree of ionization for an acidic or