if base selectionccc.chem.pitt.edu/wipf/courses/2320_06-files/if_base_selection.pdf · 8 non-ionic...

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IF. Base Selection

Boger Notes: p. 159 - 168 (Chapter VIIID)Carey/Sundberg: A p. 228-233 (Chapter A 4.8)

I. Basic Principles

pKa’s

Chemo- & Regioselectivities

Steric & Electronic Effects

Concentration Effects

Solvent Effects

Definitions

Arrhenius:[Brønsted] Bases yield OH- in [aqueous] solutions

For very strong or very weak bases, the pKa cannot bemeasured in water, since the OH- that they produce will eitherbe less than that produced by autolysis of water itself, or theywill be fully ionized, and thus appear to be all of the samestrength. This is known as the levelling effect of water.For these determinations, a range of solvents needs to beused.

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pKa Calculation

• Several theoretical approaches have been studied for the determination of theacidity/basicity of organic molecules. Most of them take advantage of thethermodynamic cycle connecting gas (gas) and aqueous (aq) phase for thecomputation of absolute pKa values of a protonated base AH+:

pKa Calculation

• for a recent application of the method of Liptak and Shields: Magill, A. M.; Yates,B. F. Austr. J. Chem. 2004, 57, 1205-1210.

• for a faster ab initio approach: am Busch, M. S.; Knapp, E.-W. ChemPhysChem2004, 5, 1513-1522.

• for the use of RP-HPLC and Hammett’s equation as well as the CaChe program(pKa’s from atomic partial charges): Hanai, T.; Koizumi, K.; Kinoshita, T.; Arora, R.;Ahmed, F. J. Chromat. A 1997, 762, 55-61. This paper also has comparative tablesfor 64 phenolic and 50 nitrogen-containing compounds.

• The average error in pKa for the first two methods is ~1 unit, vs ~1-20 for theother approaches.

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pKa Tables (Reich, UW)http://www.chem.wisc.edu/areas/reich/pkatable/index.htm

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pKa Tables (Evans, HU)http://ccc.chem.pitt.edu/wipf/MechOMs/evans_pKa_table.pdf


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pKa’s of Lithium Bases

t-BuLi 53 sec-BuLi 51 n-BuLi 50 n-Hexyl-Li 50 MeLi 48 PhLi 43

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Non-ionic Bases Phosphazene bases are extremely strong and uncharged, based on a nitrogen

atom that is doubly bonded to a pentavalent phosphorus. Through oligomerizationof the peralkylated triaminoiminophosphorane, the basicity further increases.

These bases are soluble in apolar to moderately polar solvents (hexanes, toluene,THF), solubilize weakly acidic compounds, are stable toward electrophilic attack,O2, and hydrolysis, and sterically very hindered. They are also extremelyhygroscopic.

The anions they create are considered “naked” and are therefore very reactive.The absence of metal counterions allows applications in cases where aldolreactions, epoxide-openings, hydride shifts, eliminations etc need to be avoided.They can also be quite readily recovered. Especially interesting for solutionchemistry is the Merrifield-resin-bound BEMP.

Schwesinger, R. et al. Liebigs Ann. Chem. 1996, 1055. Kraus, G. A. et al. Org.Lett. 2000, 2, 2409.

Non-ionic Bases

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Theoretical Background

Among the factors that influence the acidity of an organiccompound, HA, in the aqueous environment are:

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Acidity of Esters

Byun, K.; Mo, Y.; Gao, J., "New insight on the origin of the unusualacidity of Meldrum's acid from ab initio and combined QM/MMsimulation study." J. Am. Chem. Soc. 2001, 123, 3974-3979.

Meldrum’s acid (pKa 7.3, DMSO) is 11.7 kcal/mol more acidic thandimethyl malonate (pKa 15.9).

Acidity of Esters Meldrum’s acid (pKa 7.3, DMSO) is 11.7 kcal/mol more acidic than

dimethyl malonate (pKa 15.9).

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Acidity of Esters Meldrum’s acid (pKa 7.3, DMSO) is 11.7 kcal/mol more acidic than

dimethyl malonate (pKa 15.9).

Acid/Base Catalysis

• Specific base catalysis:the reaction rate is a function of pH, increasing as the pH is raised (I.e. [OH-].For example, in the retro-aldol reaction, the rate is a function of [OH-]:

specific basic catalysis is found for reactions in whichthere is a rapid, reversible proton removal before the rate-limiting step.

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Acid/Base Catalysis

• General base catalysis:involves bases other than OH-. For example, in the base-catalyzed bromination of acetone, the acetate buffer shows up first order in the rate equation.

General basic catalysis is found for reactions in whichremoval of a proton removal is slow, i.e. rate-limiting, and followed by a fast conversion to products.

Selective Tosylation

• Wu, Y.; Sun, Y.-P. "Novel chemoselective tosylation of the alcoholic hydroxylgroup of syn-α,β-disubstituted β-hydroxy carboxylic acids." Chem. Commun. 2005,1906-1908.

Cf. Acetoacetate dianion chemistry

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Effects of Base on Selective Alkylation ofHeterocycles

Smith, T. E.; Mourad, M. S.; Velander, A. J., "Effects of base, electrophile, and substrate on theselective alkylation of heteroaromatic systems." Heterocycles 2002, 57, 1211-1218.



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Wipf, P.; Methot, J.-L. Org. Lett. 2000, 2, 4213-4216.


Hamana, H.;Sugasawa, T.Chemistry Lett. 1983,333-336.

Whitney, S. E.;Rickborn, B., J. Org.Chem. 1991, 56, 3058.

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Effects of Base Equivalents

Prashad, M.; Liu, Y.; Repic, O. "An expeditioussynthesis of 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone by a ligand-free palladium-catalyzedα-arylation of pinacolone: Scale-up and effectof base concentration." Advanced Synthesis &Catalysis 2003, 345, 533-536.

1.6 equiv of NaO-t-Bu: SM:P1:P2:P3 = 3:81:14:3; 65% 2.5 equiv of NaO-t-Bu: SM:P1:P2:P3 = 1:94:5:3; 81% 3.0 equiv of NaO-t-Bu: SM:P1:P2:P3 = 0:97:2:1; 81%

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Effects of Base Concentration


Landini, D.; Maia, A.; Rampoldi, A. "Extractability and reactivity of hydroxide ion in low-polaritymedia under phase-transfer catalysis conditions: Dramatic effect of the aqueous baseconcentration." J. Org. Chem. 1986, 51, 5475-5476.

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Shapiro, R. H.; Duncan, J. H.; Clopton, J. C. "Effect of baseconcentration and solvent polarity on the base-catalyzeddecomposition of camphor tosylhydrazone under aproticconditions." J. Am. Chem. Soc. 1967, 89, 1442-1446.

Problem A Identify conditions for selective functionalizations at positions A,

B, and C (f. ex. alkylation). If possible, avoid protective groups.

Partial solutions: J PharmSciences, 68, 7, 1979 and JBraz Chem Soc, 9, 4, 375, 1998

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Solution A - 1

Solution A - 2

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Base in Ionic Liquids

Mehnert et al. “Preparation of C9-aldehyde via aldol condensation reactions in ionic liquidmedia” Chem. Commun. 2002, 1610-1611.

• In water, 59% of the cross-aldol product was formed in addition to 36% of the C6 homo-coupling product.• In basic [bmim][BF4], the selectivity towards the desired 2,4-dimethylhept-2-enal was 20%higher than in the NaOH-water system.• The increased selectivity was attributed to the higher solubility of 2-methylpentanal in theionic liquid phase.

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