Bowman Chem 345 Lecture Notes by Topic Cyanohydrin: Important approximate pKa’s to know for this section: pKa ~ 10 pKa ~ -5 pKa ~ 0 pKa ~ 5 pKa ~ 15 + H H O HCl H3O O 2 H SO 2 4 N R ROH R H OH R R=H or sp3 C O H C N Cyanide is a moderate base (pKa of HCN ~ 10). It is also a good nucleophile. Like Grignards and organolithiums, it can add to carbonyls. Standard conditions for cyanohydrin formation is a cyanide salt and a weak acid like acetic acid.1 KCN CN O cyanohydrin AcOH racemic OH O AcOH=acetic acid= OH Mechanism: The first step is cyanide attacking the carbonyl. Though this is not a favorable reaction pKa wise, it is still possible as an alcohol and HCN have very close pKa’s (the difference is ≤ 6). The second step is favorable as acetate is a weaker base than an alkoxide (negative O). This step you can write as reversible or not (though it is on the boundary reversible/irreversible boundary (>6 but ≤ 10). [Technically, cyanohydrins are slightly more acidic (pKa~13) than normal alcohols due to the inductive effect of the nitrile. One of the most common mistakes in this mechanism is to protonate the carbonyl. Though technically, acetic acid can barely protonate the carbonyl, the cyanide being a stronger base than acetate would rather irreversibly deprotonate a protonated carbonyl than add to the carbonyl carbon. 1 Brunner, A.; Hintermann, L. Chem. Euro. J. 2016, 22, 2787-2792 Bowman Chem 345 Lecture Notes by Topic Unlike Grignard and organolithium reactions, the cyanohydrin formation can be reversed. Add base to a cyanohydrin, and the carbonyl is reformed. (Base typically needs to have a conjugate pKa greater than or equal to 10). Remember, sodium borohydride, Grignards, and organolithiums are all basic compounds. CN Base O racemic OH Due to the reversibility of the cyanohydrin formation, it is necessary to have a proton source present at the same time as the nucleophilic carbon (the cyanide) to isolate the cyanohydrin. This is something that is a definite DO NOT DO with Grignard and organolithium reactions). Also, the proton source strength wise must be in the correct conjugate pKa range (~5-10). Too strong, and the cyanide is irreversibly protonated. Too weak an acid and the protonation step does not occur, or a side reaction such as an Aldol or benzoin condensation (to be talked about later in the semester) can occur. HCl and H2SO4 are all too strong of acids. They will irreversible protonate the cyanide, which gets rid of your nucleophile. pKa ~ -5 irreversible pKa ~ 10 reaction H Cl C N Cl H C N strong nucleophile cannot not a nucleophile acid moderate base deprotonate cannot protonate HCN a carbonyl to form a nucleophile Bowman Chem 345 Lecture Notes by Topic Alcohols are too weak of acids. The generated alkoxide upon protonation to form the cyanohydrin is too strong of a base. It will drive the reaction backwards or cause side reactions to occur. pKa ~ 15 pKa ~ 15 (actually slightly less) CN CN HO O strong base O OH drives reaction backwards or causes side reactions Cyanohydrins can be made using a moderate base (NEt3) or a catalytic amount of a strong base (NaOH). In such instances, the cyanide source is not a cyanide salt like KCN, NaCN, or LiCN, instead the cyanide cource is acetone cyanohydrin2 or HCN (gas).3 HO CN OH O CN NEt3 racemic CH Cl 2 2 2 Kumar, S.; Pearson, A. L.; Pratt, R. F. Bioorg. Med. Chem. Lett. 2001, 9, 2035-2044. 3 Kida, K. Jpn. Kokai Tokkyo Koho, 20000264859, Sep 2000 Patent Bowman Chem 345 Lecture Notes by Topic HCN cat. NaOH CN O racemic OH With the use of enzymes, optically active cyanohydrins can be formed.4,5 mandelonitrile lyase extract OH O KCN, AcOH H2O CN optically active (92 % ee) These enzymes have a tendency to be substrate specific. What works with one carbonyl, may not work with another. So, a bit of trial and error with multiple enzymes is routinely done. 4 Brovetto, M.; Gamenara, D.; Mendez, P. S.; Seoane, G. A. Chem. Rev. 2011, 111, 4346-4403. 5 Brusse, J.; Loos, W.T.; Kruse, C.G.; Van Der Gen, A. Tetrahedron 1990, 46, 979-986. Bowman Chem 345 Lecture Notes by Topic Here are some representative procedures to form cyanohydrins: Sharma, V.; Kelly, G. T.; Watanabe, C. M. H. Organic Letters 2008, 10, 4815-4818. OH NaCN O AcOH racemic N A suspension of NaCN (0.6g, 12.5mmol) in dry ethyl ether (10ml) was maintained at 0°C in an ice bath. Glacial acetic acid (0.7ml, 12.9mmol) was added drop-wise and the mixture was stirred at 0°C for 30 min. Methacrolein (Aldrich)(0.5g, 7.1mmol), was added drop-wise and the temperature was allowed to rise to room temperature overnight. A thick white precipitate was formed which was filtered under vacuum, and washed with dry ethyl ether. The filtrate was evaporated on a rotary evaporator to yield the crude cyanohydrin as a colorless oil in ~82% yield. 1H NMR & COSY (CDCl3, 300MHz) 1.82 (s, 3H), 4.20 (bs, 1H), 4.82 (s, 1H,), 5.05 (s,1H), 5.24 13 (s, 1H). C NMR & HMQC (CDCl3, 300MHz): δ17.8, 64.6, 115.3, 118.2, 139.7. IR (NaCl, thin film) cm-1 : 3415.8(br), 2922.4, 2854.3, 2250.3, 1661.2, 1448.0, 1054.3. MS (EI+)C5H7NO (M), 97.0, found 70.9 (M-CN) Brusse, J.; Loos, W.T.; Kruse, C.G.; Van Der Gen, A. Tetrahedron 1990, 46, 979- 986. mandelonitrile lyase extract OH O KCN, AcOH H2O CN optically active (92 % ee) To a solution of 15 mmol of aldehyde in 5 mL of ethanol was added, under argon, 15 mL of the enzyme extract and the mixture was cooled to 0°C. 20 mL of 1 1N KCN/HOAc buffer (pH 5.4) was mixed with 10 mL of ethanol, cooled to 0°C and added dropwise to the magnetically stirred mixture in 1.5 h. After stirring for another 3.5 h at 0°Ç, the reaction mixture was extracted with ether (3 x 25 mL). The combined ether layers were washed with a 10% NaCl solution (3 x 5 mL). Drying over MgSO4 and evaporation afforded the crude product. Bowman Chem 345 Lecture Notes by Topic Brunner, A.; Hintermann, L. Chem. Euro. J. 2016, 22, 2787-2792 O O HO KCN AcOH MeOH O OH HO CN racemic The aldehyde residue taken up in MeOH (2.0 mL) and added dropwise into a stirred solution of KCN (48.8 mg, 0.75 mmol, 1.5 equiv) in MeOH (1.00 mL) at 0 °C. After addition of AcOH (57.0 µL, 1.00 mmol, 2.0 equiv) and stirring for 10 min at 0 °C, the mixture was diluted with H2O (10 mL) and EtOAc (10 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 20 mL) and the combined organic phases were washed with H2O (20 mL) and sat aq. NaCl (20 mL). After drying (MgSO4), filtration and evaporation of the filtrate under reduced pressure gave (11-13C)-11-cyano-11- hydroxyundecanoic acid as pale yellow oil. Bowman Chem 345 Lecture Notes by Topic Kumar, S.; Pearson, A. L.; Pratt, R. F. Bioorg. Med. Chem. Lett. 2001, 9, 2035-2044. HO CN OH H N H N O CN O NEt 3 O racemic CH2Cl2 A solution of phenylacetylaminoacetaldehyde (10 g, 56 mmol) in methylene chloride (177.3 mL) under nitrogen was treated with acetone cyanohydrin (15.54 mL) and triethylamine (4.71 mL). The resulting mixture was stirred for four h. After evaporation of solvent, the residue was taken upin ethyl acetate, washed with brine and dried over MgSO4. The crude product was purified using flash column chromatography on silica gel with a hexane/ethyl acetate (1:1) mixture as solvent. The product was isolated as a pale, white brittle solid in a yield of 57% (6.56 g); 1 mp 57–58 °C, H NMR (300 MHz, CDCl3) d 3.45 (dt, J=14.2, 6.2 Hz, 1H), 3.63 (s, 2H), 4.6 (br s, 1H), 5.4 (br s, 1H), 6.4 (br s, 1H), 7.2–7.4 (m, 5H). Kida, K. Jpn. Kokai Tokkyo Koho, 20000264859, Sep 2000 Patent HCN cat. NaOH CN O racemic OH .