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 OO H2C N OO OBase Base O O Me O O Et HN O O NMe O O Et H Chem 206D. A. Evans Matthew D. Shair Monday, October 28, 2002 a73 Reading Assignment for this Lecture: Carey & Sundberg: Part A; Chapter 7Carbanions & Other Nucleophilic Carbon Species Acid-Base Properties of Organic Molecules a73 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 a73 Bronsted Acidity Concepts in the Activation of Organic Structures a73 Medium Effects on Bronsted Acidity a73 Substituent & Hybridization Effects on Bronsted Acidity a73 Kinetic & Thermodynamic Acidity of Ketones a73 Kinetic Acidity: Carbon vs. Oxygen Acids a73 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 3Acids 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 R1 R2 X C R1 R2 R3 H O R M R H R O O R SiMe3 R H R OM 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) Chem 206D. A. Evans Acidity Concepts-1 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 R 1) a73 Base Activation a73 Acid Activation + a73 The Aldol Example + + base acid Let H–X be any Bronsted acid. In water ionization takes place: + + Keq =where where [HOH] = 55.5 mol L-1 Since [HOH] is, for all practical purposes, a constant value, the aciddissociation constant K a 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) a73 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–. a73 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 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 Chem 206D. A. Evans ? G° = - RT ln K or ? G° = – 2.3 RT log10 K 2.3 RT = 1.4 at T = 298 K in kcal ? mol-1? G° 298 = - 1.4 log10 Keq with pK = – log10 K? G°298 = 1.4 pKeq ≈ 1.4 pKa Hence, pKa is proportional to the free energy change Keq pKeq ? G° 1 10 100 0 - 1 - 2 0 - 1.4 - 2.8 kcal/mol En erg y Reaction coordinate ? G° a73 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. Themore 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 vacuumdramatically reflect this trend. a73 Medium Effects HOH pKa Medium 15.7 31 279 (est)** Vacuum ** The gas phase ionization of HOH is endothermic by 391 kcal/mol !!! Substrate ? pKa 15.5 7.7 13.7 8.1 7.2 7.6 a73 Medium Effects on the pKa of HOH a73 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 ? pKa 2.1 3.1 0 4.5 sp3-orbitals 25% s-character sp2-orbitals 33% s-character sp-orbitals 50% s-character CSP3 CSPCSP2 CSP2 1 S Orbital 2 S Orbital 3 S Orbital 2 S Orbital 2 P Orbital 3 P Orbital CSPCSP3 R C O – CH2 H R RR RR H C O O – R H RR R C C O CH2–H H H H (DMSO) R H CH H H C O O H (DMSO) Chem 206D. A. Evans Acidity Trends for Carbonyl & Related Compounds Substituent Effects Electronegativity e.g. Compare Carboxylic Acids vs. Ketones pKA = 4.8 pKA ≈ 19 Carboxylate ionmore 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 Most stableLeast stable S-states have greater radial penetration due to the nodal properties ofthe 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 chargethan electrons in 2P states. ? Ra dia l P rob abi lity 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 % Ra dia l P rob abi lity ? The above trends indicate that the greater the % of S-character at a given atom, the greater the electronegativity of that atom. 2 2.5 3 3.5 4 4.5 5 Pauling Electronegativity 20 25 30 35 40 45 50 55 % S-Character C SP3 C SP2 C SP N SP3 N SP2 N SP 25 30 35 40 45 50 55 60 Pka of Carbon Acid 20 25 30 35 40 45 50 55 % S-Character CH 4 (56) C 6 H 6 (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 Chem 206D. A. Evans Acidity Trends for Carbonyl & Related Compounds 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 a73 Alkyl Substituents on Localized Carbanions are Destabilizilng: Steric hinderance of anion solvation pKA (DMSO) 29 31 pKA (DMSO) 31.1 38.3 (JACS 1975, 97, 190)Compare: Inductive Stabilization versus Lone Pair Repulsion (-I vs +M -Effect) pKA (DMSO) 30.7 27.9 19.4 Inductive Stabilization a73 Heteroatom-Substituents: - 1st row elements of periodic table a73 Heteroatom-Substituents: - 2nd row elements of periodic table pKA (DMSO) 29 20.5 12.2 Strong carbanion stabilizing effect 20.5 pKA (DMSO) S He HaH O OH He : Ha = 30 H Ph3C–HO O H SS Ha He Me Me H H HbHc C OR CH3 R O HbHc R O – Ha C S X C H H C N C H H C N P CH3 Ph Ph Ph C H H C O CH3 C H H C O CH3 S S H HS CH 3H3C O O S CH3 Me Me S CH3H3C O C H H NO2 C H H N O O Chem 206D. A. Evans Acidity Trends for Carbonyl & Related Compounds a73 Carbanion Stabilization by 2rd–Row Atoms: SR, SO2R, PR3 etc + 18.2 (DMSO) + 22.5 31 31 35 The accepted explanation for carbanion stabilization in 3rd rowelements is delocalization into vicinal antibonding orbitals (JACS 1976, 98, 7498; JACS 1977, 99, 5633; JACS 1978, 100, 200). Cn S–Xσ*E Cn (filled) S–Xσ* (empty) This argument suggests a specific orientation requirement. This has been noted: Anti (or syn) periplanar orientation of Carbanion-orbital and σ* orbital mandatory for efficient orbital overlap. He : Ha = 8.6 (JACS 1978, 100, 200) (JACS 1974, 96, 1811) pKA (DMSO)17.2 26.5 31.5 For efficient conjugative stabilization, rehybridization of carbanion orbital from nsp3 to np is required for efficient overlap with low-lying pi*-orbital of stabilizing group. However, the cost of rehybridization must be considered. a73 Conjugative Stabilization of Conjugate Base a73 Stereoelectronic Requirement for Carbanion Overlap: Enolization of Carbonyl Compounds pKA 5.2 C-H acidity notdetectable pKA (DMSO) 31.5 47.7 Rates for deprotonation with n-BuLi Stereoelectronic Requirements: The α-C-H bond must be able to overlap with pi? C–O – Ha+ base pi? C–O 2 2.2 2.4 2.6 2.8 3 3.2 Electronegativity of X 6 8 10 12 14 16 pKa of X–OH HOCl (7.5) HOH (15.7) acetone enol (10.9) phenol (10.0) Why is phenol so much more acidic than cyclohexanol? a73 a73 The Approach: a73 Is the benzene ring somehow special. i.e "larger resonance space." Acetone enol:a73 How important are inductive effects in the stabilization of C6H5O–?a73 Me H2C O –OHH2C Me X O – X OH CH3 OH CF3CH2 OH Cl OH X OH Me Me O O FG O – O – FG O FG OH O – O – O OH FG OH OH O – a73 Phenol Acidity: Chem 206D. A. Evans Phenol Acidity: An Analysis of Resonance & Inductive Effects + H+ This topic has a number of take-home lessons. Most importantly, is is a usefulconstruct on which to discuss the role of FG's in influencing the acidity of this oxygen acid. a73 How does one analyze the impact of structure on pKa of a weak acid (pKa > 0) ? + solvent(H+) ?G° En erg y (1)?G° For equilibria such as that presented above, analyze the effect of stabilizing (or destabilizing) interactions on the more energetic constituent which in this case is the conjugate base. ?G° + H + pKa (H2O) = 10 pKa (H2O) = 17+ H+?G° Loudon (pg 730): "The enhanced acidity of phenol is due largely to stabilizationof its conjugate base by resonance." – – – ?G° (stab) = 1.4(Pkaphenol – pKacyclohenanol) = 1.4(-7) = 9.8 kcal/mol from previous discussion, ? G?298 = –1.4 Log10 Keq = 1.4 pKeq (1)+ H+ acetone acetone enol acetone enolate Keq = 10-8 pKa = 10.9 The surprising facts is that the acetone enol has nearly the same pKa as phenol.Hence, the answer to the above question is no! Consider the following general oxygen acid X–OH where X can only stabilizethe conjugate base through induction: + H+ pKa(H2O) 15.5 12.4 7.5 As the electronegativity of X increasesthe acidity of X–OH increases. If you take the calculated electronegativity of an SP2 carbon (2.75) you can see that there is a linear correlation between the electronegativity of X and the pKa of X–OH. This argument suggests that the acidity of acetone enol is largely due to inductive stabilization, not resonance. a73 The Approach: a73 Resonance Effect: The degree to which substituent X: "contributes" electron density into enolate represents a destabilizing interaction: X C O – CH2 Resonance donation dominates inductive electron withdrawal as indicated by the data.a73 – + a71a71 R C O – CH2 C O O – RC C O CH2–H H H HCH H H C OH OO – XR C CH2 O – X R C O CH2–H Ph C O CH2CH3 C CH2OCH3 O Ph Ph C O CH2Ph C CH2SPh O Ph R X O – O XHR C C O O – Cl Cl Cl CHC C O – O EtO C O CH2–H C CH2–H O Me C CH2–H O Me2N – O C O CH2–H CCl Cl Cl C OH O C C O OH CH R X H O C C O OH H H H C C O OH H H C H H H Trend: O– > Me2N > OEt a71a71 a73 Inductive Effect: OEt > Me2N > H3C but (O–?) In this series of compounds, there are two variables to consider: The Analysis: pKa > 34 < 40pKa ~ 34pKa ~ 30pKa ~ 26 Case IV: Carboxylic Acids, Esters, Amides & Ketones: pKa = 4.8 pKa ~ 19 Carboxylate ionmore stabile than enolate because O more electronegative than C Case III: Carboxylic Acids vs Ketones: pKa = 4.9 pKa = 1.9 Case II: Carboxylic Acids: Inductive Effects & Carbon Hybridization Carboxylate ionstabilized by increased electron-withdrawing SP-hybridized carbon Carboxylate ionstabilized by increased electron-withdrawing CCl 3 group.pKa = 0.6pKa = 4.8 Case I: Carboxylic Acids: Inductive Effects a73 The Question: How does one analyze the impact of structure on pKa ? R = NR2 R = OR R = CR3 X = O (carboxylic acid) X = CH2 (Ketone/ester) X = NH (amide) + solvent(H+) ?G° ?G° En erg y Variables: a73 The General Reaction: Ionization of a weak acid (pKa 0) + solvent(H+)+ solvent D. A. Evans Chem 206Weak Acids: Impact of Structure on Acidity Stabilization by either resonance, induction, or both is observed:Substituents on the α-carbon: pKa = 17.1pKa = 17.7pKa = 22.9pKa = 24.4 For equilibria such as that presented above, analyze the effect of stabilizing (or destabilizing) interactions on the more energetic constituent which in this case is the conjugate base. O – O R'R + + + + + R O R' O O O H H R O R O O O R R CO O R R C R O R O R O R O R O O O EtCH3CH2 C OOR R O O O R HN O O NMe O O Et H O O O O Me Me O O O O Me Me O R OMe O OMe R O O R'R H O H O C OO R R R O R' O Lone pair orientation & Impact on pKa (DMSO) Since σ* C–O is a better acceptor than σ* C–R (where R is a carbon substituent) it follows that the (Z) conformation is stabilized by this interaction. (E) Conformer In the (E) conformation this lone pair is aligned to overlap with σ* C–R. σ* C–R σ* C–OIn the (Z) conformation this lone pair is aligned to overlap with σ* C–O. (Z) Conformer a73 Hyperconjugation: Let us now focus on the oxygen lone pair in the hybrid orbital lying in the sigma framework of the C=O plane. a73 Oxygen Hybridization: Note that the alkyl oxygen is Sp2. Rehybridizationis driven by system to optimize pi-bonding. The filled oxygen p-orbital interacts with pi (and pi*)C=O to form a 3-centered 4-electron bonding system. SP2 Hybridization The oxygen lone pairs conjugate with the C=O.a73 Lone Pair Conjugation: Rotational barriers are ~ 10 kcal/molThis is a measure of the strength of the pi bond. barrier ~ 10 kcal/mol ?G° ~ 2-3 kcal/molE ne rgy These resonance structures suggest hindered rotation about =C–OR bond. This is indeed observed: a73 Rotational Barriers: There is hindered rotation about the =C–OR bond. The (E) conformation of both acids and esters is less stable by 2-3 kcal/mol. Ifthis equilibrium were governed only by steric effects one would predict that the (E) conformation of formic acid would be more stable (H smaller than =O).Since this is not the case, there are electronic effects which must also be considered. These effects will be introduced shortly. ?G° = +2 kcal/molSpecific Case:Formic Acid (E) Conformer(Z) Conformer a73 Conformations: There are 2 planar conformations. D. A. Evans Chem 206Acidity of Carboxylic Acids, Esters, anf Lactones: Anomeric Effects Again? ?? ?? ?? ?? pKa ~ 30 pKa = 25.2 pKa = 20.6pKa = 24.5 pKa = 7.3pKa = 15.9 See Bordwell, J. Org. Chem. 1994, 59, 6456-6458 E(rel) = 0 E(rel) = +3.8 kcal Is this a dipole effect? See Bordwell Meldrum's Acid Houk, JACS 1988, 110, 1870supports the dipole argument OO Me OO MeHB HB MeOLi LiNR2 O MeHAHB HB LiNR2 H H H MeO H H MeOLi OLi MeH H O H H H HO C3H7 CH3 O O CH3C3H7 Ph CH 3 OO CH3Ph THF K A– K LiNR2B– A– OLi MeHAHB B– N Me Me Me Me Li Chem 206D. A. Evans Kinetic & Thermodynamic Acidity of Ketones a73 Kinetic Acidity: Rates of proton removal Consider enolization of the illustrated ketone under non-equilibrating conditions: kAkB Kinetic acidity refers to the rate of proton removal. e.g. k A vs k B . For example, in reading the above energy diagram you would say that HA has a lower kinetic acidity than H B . As such, the structure of the base (hindered vs unhindered) employed plays a role in determining the magnitude of k A and k B . For the case shown above, ? G ? A will increase more than ? G ? B as the base becomes more hindered since the proton H A resides in a more sterically hindered environment. The example shown below shows the high level of selectivity which may be achieved with the sterically hindered base lithium diisopropylamide (LDA). Reaction Coordinate En erg y ?G?B ?G?A B? A? Kinetic Ratio 99 : 1LDA Equilibrium Ratio 10 : 90 a73 Note that alkyl substitution stabilizes the enolate (Why??). This effect shows up in the equilibrium ratios shown above. Kinetic & Equilibrium Ratios of Enolates Resulting from Enolizationwith LDA & Subsequent Equilibration (99) (1) Kinetic Ratios Equilibrium Ratios (90)(10) (2) (98) Kinetic Ratios (34) (66) Equilibrium Ratios (13) (87) Kinetic Ratios (53) (47) Equilibrium Ratios (84)(16) Kinetic Ratios (87) (13) Equilibrium Ratios Equilibrium Ratios (1)(99) Kinetic Ratios (14) (86) a73 Hence, enolization under "kinetic control with LDA allows you to producethe less-substituted enolate while subsequent equilibration by simply heating the enolate mixture allows equilibration to the more substituted enolate. –78 °C O H Proton transfers from C-H Bonds are slow. O H Observation: The thermodynamic acidities of phenol and nitromethane are both approximately 10; however, using a common base, phenol is deprotonated 10+6 times as fast. N OOHH N O–H O H H H3C N O O N O O H H H N O O H H O H2C N O O OBase Base Base Base Ph S X O O OLi Ph S OPh O O H3O+ Ph S X O O O–H Ph S PPh 3 O O H3O+ Ph S CN O O Ph S O O O H X– Chem 206Evans, Annis a73 Kinetic Acidity Kinetic Acidity: Carbon versus Oxygen Acids Most carbon acids are stabilized by resonance. Hence significant structural reorganization must accompany deprotonation. O-H electron densityis here. O-H electron densityis still here. C-H electron densitynow resides here, and nuclei have moved to accomodate rehybridization. C-H electron densityis here. rel rate: 1 rel rate: 10+6 a73 Why??? The greater the structural reorganization during deprotonation, the lower the kinetic acidity a73 Kinetic Acidity vs. Leaving Group Ability: E1cb Elimination Reactions base rds krel = 1 krel = <10–8krel = 10+4 + pKa HX 10 9.50 Stirling, Chem. Commun. 1975, 940 The greater the structural reorganization of the leaving group during E1cb elimination, the slower the rate of elimination. + a73 Protonation of Conjugate bases Kinetic product Kinetic product Keq ~ 10 +5 Jack Hine: Least Motion Principle (Adv. Phys. Org. Chem. 1977, 15, 1)Lowry & Richardson, 3rd Edition, pp 205-206 Those elementary reactions that involve the least change in atomic posiitons will be favored pKa(H2O)~10 pKa(H2O)~10 OH OHPh + Ph CH3 OH+ S OH MeMe + 15.7 (31.2) 15.54 (27.9) t-BuOH 12.5 (23.5) (CF3)2CHOH C6H5OH 8.35m-O2NC6H4OH 7.14p-O2NC6H4OH (10.8) 10.20p-OMeC6H4OH (19.1) 2-napthol (17.1) (29.3)16.5 PhPh N OH 11.3 (20.1) N OHPh O Me (18.5) O NHPh OH (13.7)8.88 (17.9) (29.4)17 9.95 (18.0) OHR O N+ OH O+ H HMe O OHX Me O + Me H N+ O OHPh O+ H Me S OH O O Ph S OH O O+ H MePh H2O (DMSO)(DMSO)H2OH2O (DMSO) CH3CO3H MeOOH CF3SO3H (DMSO) H HO H CF3 CCl3 CHCl2 HOOH H2SO4 H2SO3 HSCN H3PO4 H2S H3O+ H2O HNO3 HNO2 HN3 NH4Cl H2CrO4 HCN CH3SO3H HClO4 HOCl HF HCl HBr B(OH)3 CH2NO2 CH2F CH2Cl CH2Br CH2I CH3 C6H5 H2O D.H. Ripin, D.A. Evans *Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods. 0.79 SULFINIC & SULFONIC ACIDS PEROXIDES pKapKapKa pKa's of Inorganic and Oxo-Acids 8.2 11.5 (11.1) (12.3) (1.6) (0.3)-14 (7.9) (12.9) (15) (1.8) (0.9) (32) cis-CO2H trans-CO2H R= 3.6, 10.3 3.77 -0.25 0.65 1.29 -8.0 11.6 -3.0, 1.99 1.9, 7.21 4.00 2.12, 7.21,12.32 7.00 -1.7 15.7 -1.3 3.29 4.72 9.24 3.17 -0.98, 6.50 9.4 -2.6 -10 7.5 -9.00 9.23 INORGANIC ACIDS Chem 206 SubstrateSubstrate 1.92, 6.23 -12.4 -7.8 -6.2 -3.8 -2.05 -2.2 -2.6 2.1 -1.8 -6.5 X= 1.68 2.66 2.86 2.86 3.12 4.76 4.2 o-O2NC6H4 m-O2NC6H4 p-O2NC6H4 o-(CH3)3N+C6H4 p-OMeC6H4 p-ClC6H4 o-ClC6H4 m-ClC6H4 2.17 2.45 3.44 2.94 3.83 3.99 1.37 p-(CH3)3N+C6H4 3.43 4.47 4.25 3.02, 4.38 Substrate Substrate PROTONATED SPECIESCARBOXYLIC ACIDS ALCOHOLS c-hex3COH 24 OXIMES & HYDROXAMIC ACIDS pKa N NH+ NH3NH3 ++ (NH) NH HN + O2N NO2 NO2 NH3+ 2.97, 8.82(2.97, 8.93) -9.0, 12.0(--, 7.50) 8.88 (13.7) N+ N+ H H NH MeMe MeMe NHMe2N NH R R H3N+ +NH 3 NHO O Bn N+ H O N+H2 HN HN NNH H2N N N N NH R NH2 O NH O NHEt Ph NH O NH O NH O O O O NH O NHPh OH Me2N NMe2 N+H2 Ph Me NNH2 O NHNH2Ph NSO2Ph NH2R H2O (DMSO) DABCO DBU Et3N+H i-Pr2N+H2 i-Pr2NH EtN+H3 TMS2NH N+H4 NH 3 TMP PhNH2 Ph2NHPhN+H3 Ph2N+H2 H2NN+H3 HON+H3 H (PPTS) DMAP PhN+(Me)2H t-Bu Me NCNH2 H CH3 Ph CF3 OEt Ac2NH PhSO2NHNH2 PhNHNHPh PhSO2NH2 MeSO2NH2 CF3SO2NH2 HN3 PhCN+H MeSO2NHPh HYDROXAMIC ACID MePh (DMSO)H2O H2O (DMSO) (DMSO)H2O 26(THF) D.H. Ripin, D.A. Evans *Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods. 38 (12) (estimate) pKa's of Nitrogen Acids Chem 206 SubstrateSubstrate Substrate pKa Substrate (41) (36 THF)) (37) (30) (10.5)9.2 10.6 11.05 10.75 (30.6) (25.0)4.6 0.78 2-napthal-N+H3 4.16 (3.6) 8.12 5.96 -9.3 5.21 (3.4) + 9.2 + 4.95 (0.90) 5.20 (2.50) R= 6.75 (4.46) 6.95 N-Me morpholine 7.38 Morpholine 8.36 (9.00) 6.90, 9.95 Quinuclidine 11.0 (9.80) Proton Sponge (20.5)12 (20.95) (18.6)(23.0) (44) (16.9) (26.5) 1,2,3 triazole (13.9) R= NH2 (urea) (23.5) (25.5) (23.3) (17.2) (26.9) (24.8) 15.1 (21.6) (17.9) Cl, H 0.72 (17.0) (24.1) (14.7)8.30 (13.6) (21.6) (18.9) (17.2) (26.1) AMIDES & CARBAMATES PROTONATED NITROGEN AMINES (17.5) (16.1) 6.3 (9.7) 4.7 (7.9) -10 (12.9) IMIDES SULFONAMIDE HYRDAZONES,- IDES, & -INES AMIDINES HETEROCYCLES PROTONATED HETEROCYCLES R= (17.3)(15.0) pKa pKa pKa GUANIDINIUM, O n Me Me MeMe Me O X O EtEt i-Pr i-Pr O O Met-Bu X O Ph Ph i-Pr O Ph O LiO Me O X O O O O MeMe O Met-BuO t-BuO O Ph EtO O N+Me3 O EtO Me O O OMeMeO O S O MeO S N+Me3 O Et2N Ph O Me2N Me2N O SPh N O CN Me2N Me S O MeMe2N O H2 HCCH H2O (DMSO) HYDROCARBONS (DMSO)H2O H2O (DMSO) (DMSO)H2O CH4 CH2=CHCH3 PhH CH2=CH2 PhCH3 Ph2CH2 Ph3CH (Me)3CH (Me)2CH2 PhCCH XC6H4CH3 HPh SPhCOCH 3SO 2Ph HCH 3 COCH3 COPh CO2Et CN OMe NPh2 N+Me3 NO2 SPh OPh SO2Ph SePh H OMeNMe 2Br CN F Ph D.H. Ripin, D.A. Evans 19-20 9 13 11 24.5 ~36 *Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods. SubstrateSubstrate Substrate pKa Substrate AMIDES pKa pKa pKa (56) (44) (43) (32.2) (30.6) 53 51 50 48 43 46 41 33.5 31.5 43 24 23 (28.8) X= p-CN p-NO2 p-COPh (30.8) (20.4) (26.9) (26.1) (18.0) (20.1) 15 20 X= (26.5)(19.8) (18.7) (13.3) (15.1) (27.1) (28.3) (27.7) (26.3) X= (22.85) (24.7) (24.4)(17.7) (12.7) (13.3) (22.7) (10.2) (21.6) (20.3) (14.6) (7.7) (16.9) (21.1) (11.4) (18.6) X= (24.7)(25.7) (27.5)(23.8) (22.0) n= 8 7 6 5 4 (27.4) (27.7) (26.4) (25.8) (25.1) (29.0) (28.1) (25.5) (32.4) (30.3) (23.6) (20.0) (14.2) (15.7) (20.9) (26.6) (25.9) (24.9) (17.2) (25.7) (18.2) KETONESESTERS [30.2 (THF)] pKa's of CH bonds in Hydrocarbons and Carbonyl Compounds Chem 206 NC X N Ph PhN N Ph PhN+ O- O Ph PhS S O O Ph X Ph S CHPh2 OO S O O MeMe CF3 S Me OO Me S S SH S S X Ph S X O S O CHPh2Ph S O XMe S NTs RPh Ph S Me NTsO S O NMe MePh Ph S Me N+Me2O S O NTs CH2ClPh Ph S + CH2Ph Me S O O i-PrCF3 Et S Et OO CF3 S OO PhSH BuSH Me3S+=O i-PrMe HPh SPh SOPhPh H PhSCH=CHCH2SPh t-Bu i-Pr Et Me RSCH2CN CN CO2Me Ph (PrS)3CH (PhS)3CH PhSCHPh2 (PhS)2CHPh MeSCH2SO2Ph POPh2SO2CF3 SO2PhSPh NO2COPh COCH3 CN Ph PhSCH2X H2O (DMSO)(DMSO)H2O H2O (DMSO) (DMSO)H2O H CH3 Ph COPh CONR2 CO2Et CN OPh N+Me3 SPh SO2Ph HCH 3t-Bu Ph CH=CH2CH=CHPh CCH COPh CCPh COMeOPh N+Me3CN NO2SMe SPhSO 2PhPPh 2 (PhSO2)2CH2Me D.H. Ripin, D.A. Evans 11 (10.3) (17.0) ≈7 10-11 *Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods. (16.3) (18.2) SULFONIUM (20.7) (14.4) (33) (24.5) (30.7)(27.6)R= SULFIMIDES & SULFOXIMINES X= (29.0)(29.0) (24.5) (18.2)(27.2) (33)X= (35.1) SULFOXIDES (26.3) (22.9) (23.6) (24.0) (24.3)R= (19.1)(20.8) (30.7)X= (30.5) (31.3) (22.8) (26.7) (23.0) (23.4) (24.9)(11.0) (20.3) (30.8)(11.8) (16.9)(18.7) (20.8) (30.8)X= SULFIDES (30.0) (30.2) (25.2) (26.7) (30.1) (28.2) SubstrateSubstrate Substrate pKa Substrate HETERO-AROMATICS NITRILES pKa pKa pKa X= (31.3) (32.5)(21.9) (10.2) (17.1) (13.1) (11.1) (28.1) (20.6) (20.8) (12.0) SULFONES X= (29.0)(31.0) (31.2)(23.4) (22.5)(20.2) (22.1)(17.8) (11.4)(12.5) (27.9) (19.4)(12.0) (7.1)(23.5) (20.5) (12.2)(20.2) (22.3) (31.1) (18.8) (21.8) (32.8) (14.3) (26.6) pKa's of CH bonds at Nitrile, Heteroaromatic, and Sulfur Substituted Carbon Chem 206 O2N n(EtO) 2P X O Ph2P O X Ph Ph N Ph PhSe Ph O O PhMeO CH2COPh CH2SO2Ph CH2SPh CH2Bn CH2Ph CHMe2 CH2Me CH3 RNO2 NITRO Ph2PCH2SO2Ph Ph2PCH2PPh2 CN SPh SiMe3 Cl CO2Et CN Ph Ph3P+CH2CN Ph3P+CH2COPh Ph3P+i-Pr Ph3P+CH3 Et3P+H MeP+H3 P+H4 PHOSPHONIUM CONEt2 CO2Et COPh SO2Ph CN Me3N+CH2X AMMONIUM PhOCH2SO2Ph PhOCH2CN MeOCH2SO2Ph CH3OPh PhSeCH=CHCH2SePh (PhSe)2CH2 PhSeCHPh2 H2O (DMSO)(DMSO)H2O H2O (DMSO) (24.3) IMINES (15.8) (17.9) (16.0) (17.8) (26.9) 7 6 5 4 3n= (7.7) (7.1) (11.8) (16.2) (12.2) (16.9) (16.7) (17.2)R= (20.3) (29.9) (16.9) (24.9)X= PHOSPHINES (28.8) (26.2) (18.6) (16.4) (27.6)X= PHOSPONATES & PHOSPHINE OXIDES (7.0) (6.2) (21.2) (22.4) 9.1 2.7 -14 (24.9) (20.6) (14.6) (19.4) (20.6)X= (21.1) (27.9) (28.1) (30.7) (49) SELENIDES ETHERS (27.2) (31.0)PhSeCH2Ph (31.3) (27.5) (18.6) D. H. Ripin, D. A. Evans SubstrateSubstrate Substrate pKapKa pKa pKa's of CH bonds at Heteroatom Substituted Carbon & References REFERENCES DMSO: JACS 97, 7007 (1975)JACS 97, 7160 (1975) JACS 97, 442 (1975)JACS 105, 6188 (1983) JOC 41, 1883 (1976)JOC 41, 1885 (1976) JOC 41, 2786 (1976)JOC 41, 2508 (1976) JOC 42, 1817 (1977)JOC 42, 321 (1977) JOC 42, 326 (1977)JOC 43, 3113 (1978) JOC 43, 3095 (1978)JOC 43, 1764 (1978) JOC 45, 3325 (1980)JOC 45, 3305 (1980) JOC 45, 3884 (1980)JOC 46, 4327 (1981) JOC 46, 632 (1981)JOC 47, 3224 (1982) JOC 47, 2504 (1982)Acc. Chem. Res. 21, 456 (1988) Unpublished results of F. Bordwell Water: Advanced Org. Chem., 3rd Ed. J. March (1985) Unpublished results of W. P. Jencks THF: JACS 110, 5705 (1988) ≈10 *Values <0 for H2O and DMSO, and values >14 for water and >35 for DMSO were extrapolated using various methods. Chem 206 Oxime ethers are ~ 10 pka units less acidic than their ketone counterparts Streitwieser, JOC 1991, 56, 1989