pKa - Brønsted acids and
bases
Solvent and structure effects
Determination of pKa values
2
Index
pKa and pKaH
Determination of pKa values
Effects on acidity and basicity
– Solvent effects
– Intrinsic stabilization of ions
– Other structure variables
Public pKa tables and further reading
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3
pKa and pKaH
𝑝𝐾𝑎 = −𝑙𝑜𝑔10 𝐾𝑎
– Where 𝐾𝑎 =
1
𝑎 𝐴− 𝑎 𝑆𝐻 +
𝑎 𝐻𝐴
𝑎 = activity, 𝑆 = solvent
– pKas in different solvents
are not directly
comparable2
𝑝𝐾𝑎𝐻 = −𝑙𝑜𝑔10 𝐾𝑎𝐻
– pKa of conjugate acid
– Measure of basicity
1) Anslyn, E. V., Dougherty, D. A. (2006) Modern Physical Organic Chemistry, University Science Books.
2) Cookson, R. F. Chem. Rev. 1974, 74, 5.
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Determination of pKa values
In solution phase1
– Potentiometric and spectrophotometric methods
– Calorimetry (Heat of protonation/deprotonation)
– Cyclic voltametry (indirect)
Major constraint is the leveling effect
– In H2O reliably between pH 1 to 131
– In DMSO up to pKa of 32 (pKa = 35,1 in DMSO)2
– Extrapolation with acidity functions (e.g. H0 and H_)1
1) Cookson, R. F. Chem. Rev. 1974, 74, 5.
2) Olmstead, W. N; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295.
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Determination of pKa values
Potentiometric methods1
– Electromotive force (emf) is proportional to Ka
• Accurate in aqueous solutions
• In non-aqueous solvents, such as THF, ion pairing and
aggregation may affect the measurements2
• Right choice of electrode
– pKaHs of weak acids in DMSO3
• Glass electrode (Ag/AgClO4/DMSO)
• Titration with Cs(CH3SOCH2)/DMSO
1) Cookson, R. F. Chem. Rev. 1974, 74, 5.
2) Garrido, G.; Koort, E.; Ràfols, C.; Bosch, E.; Rodima, T.; Leito, I; Rosés, M. J. Org. Chem. 2006, 71, 9062.
3) Ritchie, C. D.; Uschold, R. E. J. Am. Chem. Soc. 1967, 89, 1721
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Determination of pKa values –
Equilibriation methods
Relative to a reference compound (e.g. pyridine)1
UV/Vis spectrophotometry, NMR
ΔpKaH determined from equilibrium constant K
– Titration with a strong acid
– ∆𝑝𝐾𝑎𝐻 = 𝑝𝐾𝑎𝐻
𝑎
HB2 + − 𝑝𝐾𝑎𝐻 HB1 + = 𝑙𝑜𝑔
𝑎
HB2 + 𝑎 B1
HB1 + 𝑎 B2
MSAD (McEwen-Streitwieser-Applequist-Dessy)2
– Introduced by D. J. Cram in 1965
– Relative acidities against 9-phenylfluorene from equilibrium
concentrations in cyclohexylamine/cyclohexylamide
– UV-Vis
1) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
2) Cookson, R. F. Chem. Rev. 1974, 74, 5.
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Determination of pKa values –
Equilibriation methods
Continuous
basicity scale
from interlocking
measurements
– Relative to a
standard basicity
Picture taken from : Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.;
Mäemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
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Determination of pKa values
Voltammetric reduction potentials
– Preliminary work by Breslow1,2
– pKa is indirectly observed
1) Breslow, R.; Chu, W. J. Am. Chem. Soc. 1970, 92, 2165.
2) Breslow, R.; Chu, W. J. Am. Chem. Soc. 1973, 95, 411.
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Solvent effects
Gas phase acidities
– Only intrinsic effects – Enthalpy of dissociation1
Solvation
– Lack of intrinsic stabilization decreases neutral acid strength
in aprotic solvents
– Cationic acids exhibit similar acidities in water and in
coordinating organic solvents (DMSO, DMF, THF, not MeCN)
• For substituted pyridine conjugate acids2:
– 𝑝𝐾𝑎 MeCN = 6.04 + 1.269 ∗ 𝑝𝐾𝑎 H2 O
– 𝑝𝐾𝑎 MeCN = 7.44 + 0.934 ∗ 𝑝𝐾α THF
1) Himmel, D.; Goll, S. K.; Leito, I.; Krossing, I. Angew. Chem. Int. Ed. 2010, 49, 6885.
2) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
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Solvation and ion pairing
Ion pairing and aggregation have a significant
influence on pKa1
– pKα - ion-pairing corrected pKa of ion-pair acidities
– Complexing agents, such as crown ethers, can be used to
break aggregates and ion pairs
Acidity of acetylacetone increases with increased ion
pairing of the conjugate base2
– Li+>Na+>K+
1) Olmstead, W. N; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295.
2) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
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Aggregation
Protophobic solvents
solvate cationic acids
poorly1
– Aggregation
(homoconjugation)
– Ion pairing
– Several equilibria
1) Kolthoff, I. M. Anal. Chem. 1974, 46, 1992.
2) Coetzee, J. F. ; Padmanabhan, G. R. J. Am. Chem. Soc. 1965, 87, 5005.
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Structure variables
Delocalization, inductive effects and polarizability
– Phosphazenes, Benzoic acids (Hammett), TFA, and HI
Internal solvation (field effects)
– Diols (e.g. Taddol type, acid), Enzyme active sites, Diamines
(base)
Bond angles
– Strained cyclic and bridged systems
Hybridization and aromaticity
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Delocalization and inductive effect
Inreased
delocalization
raises pKaH of
phosphazenes1
Inductive effect
stabilizes
localized charges
Polarizability
stabilizes charges
pKa (DMSO)
CH3CH2OH2
29.8
CF3CH2OH3
23.5
(CH3)2CHOH2
30.3
(CF3)2CHOH3
17.9
(CH3)3COH2
32.2
(CF3)3COH3
10.7
1) Kaljurand, I.; Kütt, A.; Sooväli, L.; Rodima, T.; Mäemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
2) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3295.
3) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
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Intramolecular H-bonding (field
effects)
Intramolecular H-bonding
increases diol acidity
– TADDOL derivative TEFDDOL1
Intramolecular H-bonding
increases diamine basicity2
Relief of lone pair repulsion
increases basicity further3
1) Christ, P.; Lindsay, A. G.; Vormittag, S. S.; Neudörfl, J.-M.; Berkessel, A.; O’Donoghue, A. M. C. Chem. Eur. J. 2011, 17, 8524.
2) Alder, R. W.; Eastment, P.; Hext, N. M.; Moss, R. E.; Orpen, A. G.; White, J. M. J. Chem. Soc. Chem. Commun. 1988, 1528.
3) Alder, R. W. Chem. Rev. 1989, 89, 1215.
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Bond angles and hybridization1
Deviation from tetrahedral geometry decreases amine
basicity
Nitrogen basicity decreases as s-character increases
1) Alder, R. W. Chem. Rev. 1989, 89, 1215.
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Aromatic stabilization vs. antiaromatic
destabilization
Cyclopentadiene1
1,2,3-triphenyl
cyclopropene2
– Antiaromatic
destabilization proposed
to have major effect
Cyclopropenimine3
– Exceptionally high pKaH
value – comparable to
phosphazenes
1)
2)
3)
4)
Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
Breslow, R; Chu, W. J. Am. Chem. Soc. 1973, 95, 411.
Bandar, J. S.; Lambert, T. H. J. Am. Chem. Soc. 2012, 134, 5552.
Coetzee, J. F.; Padmanabhan, G. R. J. Am. Chem. Soc. 1965, 87, 5005.
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Public pKa tables and reading
Reich (Bordwell)
– Extensive collection of pKa values in DMSO
– http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
Ripin & Evans (Bordwell)
– Common acids and bases (H2O and DMSO)
– http://evans.harvard.edu/pdf/evans_pka_table.pdf
Ivo Leito, University of Tartu
– Vast amounts of experimental data in organic solvents and
gas phase
– http://tera.chem.ut.ee/~ivo/HA_UT/
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Public pKa tables and reading
ZirChrom
– Aqueous pKa values for natural products, amino acids and
APIs
– http://www.zirchrom.com/organic.htm
NIST
– Gas phase acidity search engine
– http://webbook.nist.gov/chemistry/acid-ser.html
“Acid-Base Behavior in Aprotic Organic Solvents”
– Davis, M. M. (1968) National Bureau of Standards,
Washington, University of North Texas Digital library
– http://digital.library.unt.edu/ark:/67531/metadc13152/m1/1/
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Conclusions
Vast amounts of pKa data available
– Right interpretation essential
“Unified pH in all phases”1
– Relative to energy of H+ in gas phase, μabs(H+) = 0
Picture taken from: 1) Himmel, D.; Goll, S. K.; Leito, I.; Krossing, I. Angew. Chem. Int. Ed. 2010, 49, 6885.
April 3, 2012
Antti Neuvonen