D. A. Evans Acid-Base Properties of Organic Molecules Chem 206 http://ww.courses.fasharvardedu/-chem206/ Articles on the Acidities of Organic Molecules Lowry Richardson: 3rd Edition, Chapter 3 Chemistry 206 Acids and Bases Advanced Organic Chemistry Equilibrium acidities in DMSO Solution", F. G Bordwell Acc.chem.Res.1988,21,456-463 Here is a web site containing Brodwell pKa data ecture Number 17 http://www.chem.wiscedu/areas/reich/pkatable/index.htm Acid-Base Properties of Organic Molecules ■ Problems of the Day Bronsted Acidity Concepts in the Activation of Organic Structures counterparts 2 and 4. (.Org. Chem. 1994, 59, 6A57 heir acyclic Explain why 1 and 3 are4 pKa units more acidic than a Medium Effects on Bronsted Acidity Substituent& Hybridization Effects on Bronsted Acidity Kinetic Thermodynamic Acidity of Ketones 3HNo 4 Me Kinetic Acidity. Carbon vs Oxygen Acids Tabulation of acid dissociation Constants in dmso Reading Assignment for this Lecture The thermodynamic acidities of phenol and nitromethane are both 10; however, using a common base, phenol is deprotonated 10 Carey& Sundberg: Part A; Chapter 7 times as fast. Rationalize Carbanions& Other Nucleophilic Carbon Species Equilibrium acidities in DMSO Solution", F.G. Bordwell pKa(H2O) Acc.Chem.Res.1988.21.456463 rel rate: 10*6 Matthew d. shair October 28. 2002 pKa(H2O) H3C
http://www.courses.fas.harvard.edu/~chem206/ http://www.chem.wisc.edu/areas/reich/pkatable/index.htm O H The thermodynamic acidities of phenol and nitromethane are both ~10; however, using a common base, phenol is deprotonated 10+6 times as fast. Rationalize H3C N O O H2C N O O O Base Base O O Me O O Et HN O O N Me O O Et H D. A. Evans Chem 206 Matthew D. Shair Monday, October 28, 2002 ■ Reading Assignment for this Lecture: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Acid-Base Properties of Organic Molecules ■ Problems of the Day: Articles on the Acidities of Organic Molecules Chemistry 206 Advanced Organic Chemistry Lecture Number 17 Acid-Base Properties of Organic Molecules ■ Bronsted Acidity Concepts in the Activation of Organic Structures ■ Medium Effects on Bronsted Acidity ■ Substituent & Hybridization Effects on Bronsted Acidity ■ Kinetic & Thermodynamic Acidity of Ketones ■ Kinetic Acidity: Carbon vs. Oxygen Acids ■ Tabulation of Acid Dissociation Constants in DMSO "Equilibrium acidities in DMSO Solution", F. G. Bordwell. Acc. Chem. Res. 1988, 21, 456-463. Here is a web site containing Brodwell pKa data Explain why 1 and 3 are ~4 pKa units more acidic than their acyclic counterparts 2 and 4. (J. Org. Chem. 1994, 59, 6456) 1 2 3 4 Lowry & Richardson: 3rd Edition, Chapter 3 Acids and Bases "Equilibrium acidities in DMSO Solution", F. G. Bordwell. Acc. Chem. Res. 1988, 21, 456-463. rel rate: 1 rel rate: 10+6 pKa(H2O) ~10 pKa(H2O) ~10
D. A. Evans Acidity Concepts-1 Chem 206 Activation of Organic Molecules ■ Definition of ka Let H-x be any bronsted acid. In water ionization takes place ■ Base Activation H-X HOH H30+X base Nucleophile where HoH]=55.5 mol L H-baseo Ri where Keg: HH301X HX叶HOH Since [ HOH is, for all practical purposes, a constant value, the acid dissociation constant Ka is defined without regard to this entity. e. g pKa, describes quantitatively a molecule's propensity to act as an acid, ie to release a proton. H"+X- where H=H30 Medium effects Hence Structural effects (influence of substituents R1) From the above definitions, Ka is related to Keg by the relation Acid activation Ka(H-x)=55.5 Keq(H-x acid(protic or lewis acid R2 号 electrophile|■ Autoionizationofwater IOH+ HOH 5 H30+HO" X=e.gO, NR Eq C ■ The Aldol Example Since pKa is defined in the following equation base catalys Ka=-log1o[Kal The pKa of HOH iS 15.7 Keep in mind that the strongest base that can exist in water is HO Lets now calculate the acid dis constant for hydronium ion H3o H20 0 Ca 10*5 Activation SiMe obviously cid catalysis Ka[HOH]X Keg hence Ka=55.5 pKa=-log1o Ka=-1.7 The strongest acid that can exist in water is H3O
R1 R2 X C R1 R2 R3 H O R M R H R O O R SiMe3 R H R O M O R R H R O C R1 R2 R3 R1 R2 X acid R R O R OH R R O R O M R R O R O SiMe3 HOH H–X H3O + HOH H–X HOH [H3O + ] [X– ] [H–X] [HOH] H2O [H+ ] [X– ] H3O + H + H3O + X– HO– X– H3O + (B) H2O (C) (A) D. A. Evans Acidity Concepts-1 Chem 206 Activation of Organic Molecules base - H-base pKa , describes quantitatively a molecule's propensity to act as an acid, i.e. to release a proton. acid (protic or lewis acid) Nucleophile Electrophile X = e.g. O, NR ... - Medium effects - Structural effects (influence of substituents R1 ) ■ Base Activation ■ Acid Activation + ■ The Aldol Example + + base acid Let H–X be any Bronsted acid. In water ionization takes place: + + where Keq = where [HOH] = 55.5 mol L-1 Since [HOH] is, for all practical purposes, a constant value, the acid dissociation constant Ka is defined wilthout regard to this entity. e.g. + where H+ = H3O + Hence [H–X] Ka = From the above definitions, Ka is related to Keq by the relation: Ka (H–X) = 55.5 Keq(H–X) ■ Autoionization of water + + Keq = 3.3 X 10–18 From Eq C: Ka = 55.5 Keq = 55.5(3.3 X 10–18) Hence Ka = 1.8 X 10–16 Since pKa is defined in the following equation: pKa = – log10 [Ka] The pKa of HOH is + 15.7 Keep in mind that the strongest base that can exist in water is HO– . ■ Definition of Ka pKa = – log10 Ka = –1.7 Ka = [HOH] x Keq obviously: Keq = 1 + Lets now calculate the acid dissociation constant for hydronium ion. + Ka = 55.5 The strongest acid that can exist in water is H3O + . hence base catalysis acid catalysis Ca 10+6 Activation
D. A. Evans Acidity Trends for Carbonyl Related Compounds Chem 206 I The Gibbs Relationship a Medium Effects on the pKa of HOH AG°= RTIo K HOH pKa Medium 23RT=14 The gas phase ionization of HOH is HOH or△G°=-23RTg1K att= endothermic by 391 kcal/mol !! DMSO in kcal. mor1 △G298=-14l0g1 279(est) Vacuum Representative pKa Data △G298=14pk≈14pK Substrate HOH Hence, pKa is proportional to the free energy change 7. 7.7 0 290 13.7 C6H5OH 18.0 99 8.1 2. 8 kcal/mol Reaction coordinate O2N-CH3 17.2 7.2 I Medium Effects Consider the ionization process Ph-C-CH 246 7.6 H-A solvent= A:+ solvent(H) The change in pKa in going from water to DMSO is increasingly diminished as the conjugate base becomes resonance stabilized(Internal solvation) In the ionization of an acid in solution, the acid donates a proton to the medium. The more basic the medium, the larger the dissociation equilibrium. The ability of the medium to stabilize the conjugate base also plays an important role in the promotion of ionization. Let us consider two solvents, HOH and DMSO and the performance of ubstrate HOH these solvents in the ionization process. 160 2.1 The Protonated Solvent Conjug Base Stabiliz 0→H—A 164 DMSo HO-S+ No H-bonding Capacity 133 As shown ough HOH can stabilize anions via H-bonding, DMSO cannot NCCN 11.1 11.2 will show a greater propensity to dissociate in HOH. As illustrated below the acidity constants of water in HOH, DMSO and in a vacuum dramatically reflect this trend
31.2 14.7 29.0 18.0 17.2 24.6 17 10.0 9.9 15.3 7.0 15.7 18.1 16.0 13.3 8.9 16.4 13.3 11.1 11.2 H A H O + H H S + Me Me HO O H H A – HA A EtO OEt O O Me Me O O HOH C6H5OH NC CN HSH MeOH O2N–CH3 Ph C O CH3 DMSO DMSO HOH HOH HOH DMSO D. A. Evans Chem 206 D G° = - RT ln K or D G° = – 2.3 RT log10 K 2.3 RT = 1.4 at T = 298 K in kcal × mol-1 D G°298 = - 1.4 log10 Keq with pK = – log10 D G°298 = 1.4 pKeq » 1.4 pKa K Hence, pKa is proportional to the free energy change Keq pKeq D G° 1 10 100 0 - 1 - 2 0 - 1.4 - 2.8 kcal/mol Energy Reaction coordinate D G° ■ The Gibbs Relationship Consider the ionization process: + solvent + solvent(H+ A: ) – In the ionization of an acid in solution, the acid donates a proton to the medium. The more basic the medium, the larger the dissociation equilibrium. The ability of the medium to stabilize the conjugate base also plays an important role in the promotion of ionization. Let us consider two solvents, HOH and DMSO and the performance of these solvents in the ionization process. The Protonated Solvent Conjug. Base Stabiliz. Water DMSO No H-bonding Capacity As shown above, although HOH can stabilize anions via H-bonding, DMSO cannot. Hence, a given acid will show a greater propensity to dissociate in HOH. As illustrated below the acidity constants of water in HOH, DMSO and in a vacuum dramatically reflect this trend. ■ Medium Effects HOH pKa Medium 15.7 31 279 (est)** Vacuum ** The gas phase ionization of HOH is endothermic by 391 kcal/mol !!! Substrate D pKa 15.5 7.7 13.7 8.1 7.2 7.6 ■ Medium Effects on the pKa of HOH ■ Representative pKa Data Acidity Trends for Carbonyl & Related Compounds The change in pKa in going from water to DMSO is increasingly diminished as the conjugate base becomes resonance stabilized (Internal solvation!). Substrate D pKa 2.1 3.1 0 4.5
D. A. Evans Acidity Trends for Carbonyl Related Compounds Chem 206 Substituent Effects Electrons in 2S states see"a greater effective nuclear charge than electrons in 2P states Electronegativity e.g. Compare Carboxylic Acids vs. Ketones This becomes apparent when the radial probability functions for S and P-states are examined: The radial probability functions for the hydrogen atom s& p states are shown below 0- more stabile 100% 100% enolate because electronegative than C pKA=4.8 pKA≈19 (DMSO) O Orbital 2 S Orbital Hybridization -S-character of carbon hybridization 〓2 P Orbital sp-orbitals 25%s-character sp-orbitals 33%S-character sp-orbitals 50%S-character 3 S Orbital O> 3 POrbital C∧ Carbon acids S-states have greater radial penetration due to the nodal properties of the wave function. Electrons in s states see a higher nuclear charge The above observation correctly implies that the stability of nonbonding electron pairs is directly proportional to the of S-character in the doubly occupied orbital Hybridzation Carbanions (DCsP3 (DCsP2 DCsp Bond angle 180° 20° ≈120 Least stable Most stable pK(DMSO) 23 Carbenium ions Most stable <t Least stable The above trends indicate that the greater the of S-character at a give atom, the greater the electronegativity of that atom
sp3 -orbitals 25% s-character sp2 -orbitals 33% s-character sp-orbitals 50% s-character CSP3 CSP2 CSP CSP2 1 S Orbital 2 S Orbital 3 S Orbital 2 S Orbital 2 P Orbital 3 P Orbital CSP3 CSP R C O – CH2 H R R R R R H C O O – R H R R R C C O CH2–H H H H (DMSO) R H H C H H C O O H (DMSO) D. A. Evans Acidity Trends for Carbonyl & Related Compounds Chem 206 Substituent Effects Electronegativity e.g. Compare Carboxylic Acids vs. Ketones pKA = 4.8 pKA » 19 Carboxylate ion more stabile than enolate because O more electronegative than C Hybridization - S-character of carbon hybridization Remember: Hybridzation pKa (DMSO) Bond Angle sp sp2 » sp2 sp3 180° 120° 109° 23 32 » 39 50 » 120 Carbon Acids Carbenium ions Carbanions Most stable Least stable Least stable Most stable S-states have greater radial penetration due to the nodal properties of the wave function. Electrons in s states see a higher nuclear charge. The above observation correctly implies that the stability of nonbonding electron pairs is directly proportional to the % of S-character in the doubly occupied orbital. Electrons in 2S states "see" a greater effective nuclear charge than electrons in 2P states. Å Radial Probability 100 % This becomes apparent when the radial probability functions for S and P-states are examined: The radial probability functions for the hydrogen atom S & P states are shown below. 100 %Radial Probability Å The above trends indicate that the greater the % of S-character at a given atom, the greater the electronegativity of that atom
Evans Acidity Trends for Carbonyl Related Compounds Chem 206 Hybridization Vs Electronegativity Substituent Effects There is a linear relationship between %S character Pauling electronegativity I Alkyl Substituents on Localized Carbanions are Destabilizing: Steric hinderance of anion solvation JAcs1975,97,190) PhSOz- CH-H 29 31.1 383 a Heteroatom-Substituents:- 1st row elements of periodic table pKA (DMSO) 253035 Inductive stabilization versus %S-Character PhSO2-CH-OCH3 30.7 Lone Pair Repulsion l vS+M-Effect) There is a direct relationship between %S character H PhSo2-CH-OPh 27.9 PhSo2-CH-NMe3 19.4 Inductive Stabilization H Seomx a Heteroatom-Substituents:-2nd row elements of periodic table c6H(4 Strong carbanion stabilizing effect pKA ( DMSO) PhCC-H(29) PhSo2-CH-H PhSO2- CH-SO2Ph 12.2 PhSoz CH-SPh 20.5 PhSo2-CH-PPh2 20.5
2 2.5 3 3.5 4 4.5 5 Pauling Electronegativity 20 25 30 35 40 45 50 55 % S-Character CSP3 CSP2 CSP NSP3 NSP2 NSP 25 30 35 40 45 50 55 60 Pka of Carbon Acid 20 25 30 35 40 45 50 55 % S-Character CH4 (56) C6 H6 (44) PhCC-H (29) S S H H S S Me H PhSO2-CH-OCH3 H PhSO2 -CH–H H PhSO2 -CH–Me H PhSO2-CH-OPh H PhSO2-CH-NMe3 H PhSO2-CH-H H PhSO2-CH-SPh H PhSO2-CH-SO2Ph H PhSO2-CH-PPh2 H D. A. Evans Acidity Trends for Carbonyl & Related Compounds Chem 206 There is a linear relationship between %S character & Pauling electronegativity Hybridization vs Electronegativity There is a direct relationship between %S character & hydrocarbon acidity Substituent Effects ■ Alkyl Substituents on Localized Carbanions are Destabilizilng: Steric hinderance of anion solvation pKA (DMSO) 29 31 pKA (DMSO) 31.1 38.3 Compare: (JACS 1975, 97, 190) Inductive Stabilization versus Lone Pair Repulsion (-I vs +M -Effect) pKA (DMSO) 30.7 27.9 19.4 Inductive Stabilization ■ Heteroatom-Substituents: - 1st row elements of periodic table ■ Heteroatom-Substituents: - 2nd row elements of periodic table pKA (DMSO) 29 20.5 12.2 Strong carbanion stabilizing effect 20.5 pKA (DMSO)