Hydroboration-Oxidation of (1R)-(+)-a-Pinene to lsopinocampheol

A Microscale Experiment that Displays Regio- and Stereochemistry Using NMR Spectroscopy and Molecular Mechanics Calculations
Ronald L. Blankespwr and Kenneth Piers Calvin College, Grand Rapids, MI 49546 The hydrohoration-oxidation of alkenes is a n important route to alcohols and therefore receives considerable treatment in standard organic textbooks. Although this synthetic method exhibits both regiochemistry (i.e., anti-Markovnikov addition) and stereochemistry (i.e., syn-addition) if a suitable alkene is chosen, we are not aware of an example that displays both of these features that has been adapted for use in the undergraduate laboratory. Experiments demonstratine of this seauence of reac-onlv .the r e e i o c h e m i s t ~ tions have appeared in this Juurnal in the macroscale settine(11and in laboratorv textbooks in themicrosc~lesettine (2,>). w e searched, then, for an alkene that would undergo the hydroboration-oxidation process in a manner that would demonstrate both the regio- and stereochemical features of the reaction. Our choice of (1R)-(+)-a-pinene (I), hereafter referred t o as a-pinene, as the substrate not only meets these requirements but has other advantages as well (see Fig. 1).Hydroboration-oxidation of 1 produces isopinocampheol (2) in high yield (4). Alcohol 2 is a low-melting solid that can be easily purified by sublimation in milligram quantities. This important purification technique is utilized rather infrequently in many undergraduate laboratories and needs more exposure. Another advantage in using 1 as the substrate is that it is commercially available in high optical purity. This urovides the oution of monitorine the reaction with a polarImeter. ina all;, i t should be notkd that proton NMR coupling constants for the rigid, bicyclic alcohol 2 can be calculated accurately using molecular mechanics methods (5-8). In this wav, the observed coupling constants in the NMR spectrum of the product can be compared with those calculated by the molecular mechanics program and used to help establish the stereochemistry of the product. Considerable interest in intenatinn computational methods into the undergraduate chkmistry cu&culum has been expressed in this Journal (9-13), and we believe this experiment utilizes these technologies in a meaningful way in the laboratory.

Figure 1. Compounds of

interest in this experiment

Materials and Reagents Required Standard micrwcale kit including a dry l-mL syringe. Sublimation apparatus (125-mL filtering flask fitted with a onehole rubber stopper containing a 15-mL conical centrifuge tuhe). (1R)-(+)-n-pinene, optical purity 98+%. Borane-THF complex, 1.0 M (caution: avoid contact with water). 30%H20z(caution: strong oxidant, avoid skin contact). Procedure Hydroboration. Add 150 mg (1.10 mmol) of (1R)-(+)-a-pineneto a dry 5-mL conical vial. Equip the vial with a magnetic stirrer, a Claisen head fitted with a CaC1. drvine tuhe. and a rubber seotum. ksing a dry ayringp, add 600 UL 660;; mmh) of 1.0 M HH ~ T H F rcaution: hydrogen gas is produced upon contact with warerl t o rhe

rial through the rubber septum.' While stirring, heat the reaction mixture to -50 O C for 5-10 min. Cool the reaction mixture in an ice bath. remove the rubber seotum. and. while stirrine. ... add a sin& dntpbf H.O. Cmsidernhle frkhing may occur due to the pruductkn 01hydrogen gas: After hubbling diminishes,add two mare drops of water. Oridation. Attach a condenser to the 5-mL vial containing the readion mixture. While stirring,use asyringe toadd 375rL of 3.0 M NaOH through the top of the condenser all at once, fallowed by 375 pL of 30%Hz02(caution: this reagent causes instant hums to skin). The oxidation of the dialkylhoraue with hydrogen peroxide is mildly exothermic. Heat the reaction mixture to a gentle reflux for 15-20 min. lsolatim o/ Produrr. Cool the reartion mixture in an ice bath, and transfer the aqueous layer to a 3-mL vial with a Pasrrur pipet, saving the organic layer in the reartion vial. Extract the aqueous
DUBto steric factors adialkylborane rather than atrialkylborane is f alkene to formed in the reaction, thereby requiring a 2 1 mole ratio o borane. Any hydrlde that may be present will react with water producing
hWogen gas.

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layer with 1.5 mL of petroleum ether. Discard the aqueous layer, and transfer the petroleum ether extract to the first vial containing the organic laver. Extract this solution with 2.0 mL of 0.20 M HC1 failowed h i water (2 X 1.0 mL), saving the organic layer in each case. Dry the organic layer over anhydrous NagSO*. Transfer the organic layer to a dry 125-mL Buchner filtering flask, and remove the solvent by evaporation in a hood under a slow stream of air, leaving a viscous liquid that partially solidifies upon cooling. Purification of the Product by Sublimation. Drill a hole large enough to accommodate a 15-mL glass centrifuge tuhe in a #5 rubber stopper. Place the centrifuge tube into the rubber stopper to a depth such that when the stopper is placed into the 125-mL Buchner flask containing the crude product, the bottom of the centrifuge tuhe is about 1in. from the bottom of the Buchner flask. Fill the centrifuge tube with small chips of ice. Connect the side arm of the Buchner flask to a water aspirator,and immerse the Buchner flask in a water bath (a half-full 400-mL heaker works well) maintained at about 60 'C on the hot plate. The product sublimes onto the cold surface of the centrifuge tuhe." Results and Dlscusslon The alcohol isolated from the hydroboration-oxidation of cl-pinene using the above procedure has a melting point of 51-53 O C and can be obtained in a yield of 50-60%. The proton and C-13 NMR spectra of this product (Fig. 2) show that a single substance is formed demonstrating that the reaction is hiehlv . reeio- and stereosnecific. The fact t G t asinglealcohol is fo;med in high yield in this reaction sueeests that the additionof H~0occursexclusivel~~ from the l e i sterically hindered face of the double bond ih a-ninene. Thus, onlv alcohols 2-5 are considered as ~ o s s i b l e prbducts.'l'he alcoh;ls2 and 3are the result o f a n t i - ~ a r k o v nikov addition in a syn and anti fashion respectively, whereas alcohols 1 and 5 are the result of Markovnikov addition. It is clear that the product of the reaction is neither cis-2pinanol(4) nor trans-2-pinanol(5). Not only are their melting points higher than that of the product, but the proton NMR spectrum shows a signal (a doublet of 1:2:1 triplets with J = 8.5 and 5.0 Hz, respectively) a t approximately 4 ppm for one hydrogen. The chemicalshift of this hydrogen is in the range expected for a secondary alcohol proton (CHOH). Such a sienal should be nresent in the PMR snecFlgure 2. Roton and G13 NMR spectra of alcohol 2 recorded on a 250-MHz d 5 . trum ofeither 201 3 b u t absent in hespectraof both4 k spectmmeter. Furthermore. the PMR of the nroduct disolavs a doublet at 1.05 ppm, which integrates foithree hydrbgek. This signal is attributed to a methyl group attached to a tertiary carhon stanta for the secondary alcohol (CHOH) proton were ob(CH7CH) and would be expected in the PMR spectrum of tained. The calculation suggests that this proton in 2 should either 2 or 3 but not in the spectrum of either 4 or 5. On this be coupled to three vicinal protons with coupling constants basis we may conclude that the reaction involves anti-Marof 9.7,4.3 and 3.9 Hz. This is in very good agreement with the kovnikov addition of water across the double bond. experimental spectrum we obtained for the product of the With the regiochemistry of the hydroboration-oxidation hydroboration-oxidation reaction. Similarly, the geometry of a-pinene now established, we are left with the question of of the alcohol 3 was energy-minimized and the coupling stereochemistry. Since the melting points and specific rotaconstant for the secondary alcohol (CHOH) proton obtions of isopinocampheol (2). the syn-addition product, and tained. The calculation suggests coupling to three neighborneoisopinocampheol (3), the anti-addition product, are ing protons with coupling constants of 9.7, 8.4, and 3.9 Hz. quite similar, we decided to try to use proton NMR spectra Once aeain this aerees well with the exnerimental result correlated with molecular mechanics calculations to distinobtained for the &coho1 3. The calculaied and observed guish between these two possible products. coudinp constants for this proton in 2 and 3 are summarized A small amount of isoninocamoheol (2). was converted in the table. These resu~tshemonstrate that molecular meinto the corresponding ketone (p$ridini&chlorochromate chanics calculations can have considerable utility in makine oxidation). Reduction of this ketone (LiA1H.J produced a stereochemical assignments. On the basis of these results we 20:80 mixture of isopinocampheol (2), and its epimer, neoimay conclude that hydroboration-oxidation of (lR)-(+)-clsopinocampheol(3), respectively. The PMR spectra of both pinene involves syn-addition of water across the double 2 and 3 contain a signal in the 4-ppm region attributable to a bond. secondary alcohol proton (CHOH). However, the proton in 2 is coupled to three vicinalprotons with coupling constants of 8.5, 5.0, and 5.0 Hz and occurs as a doublet of triplets cenlnltlally, the product condenses on the cold tube as a liquid that tered a t 4.05 ppm. The corresponding proton i n 3 also is f long. freezes. Then deposition occurs resulting In the formation o coupled to three vicinal protons but with coupling constants white needles. The melting points of these two sources of sublimed of 9.7, 9.7, and 5.1 Hz and appears as a triplet of doublets product are nearly Identical. centered a t 4.4 ppm. Thls software. PC Model, b available at Serena Software (Box Using the MM2 force field calculations," the geometry of 3076, Bloomington, IN 47402-3076) and can be used on IBM or the alcohol 2 was energy-optimized, and the coupling conMacintosh personal computers.
694

Journal of Chemical Education

Coupllng Constants (Hz) for H, In Alcohols 2 and 3

~lcohot
2

mans
HrHa H3-HI' HrH+ HrHa HsH,'

Dihedral Angle (') (calc)d

131 6 124 1 124

to determine independently the MM2 force field calculated coupling constants for the secondary alcohol (CHOH) proton.
J ~ S

Jdva

4.4 9.7 3.9 8.4 3.9

5.0 8.5 5.0 9.7 5.1

We are grateful to the National Science Foundation for a grant (USE-8851202) to purchase a high-field NMR spectrometer.
~~

1. Kabslks,G. W.; HdgecoeX, H.C..I Chem.Educ. 1915.52745. Butcher. S. S. Microsrole Orsonic Lobnrafnw, 2nd rd.; 2. Maw. D. W.: Pike. R. M.:

At Calvin College this experiment is done early in the second semester of organic chemistry soon after students are introduced to NMR spectroscopy. Before students do the experiment, they are told that alcohols 2-5 are possible products of the hydrohoration-oxidation of a-pinene. Based upon the PMR spectrum of the product and the coupling constants in the table, students are required to deduce the structure of the alcohol. In the near future, we hope to have a computational chemical laboratory that will allow students

4. Brown,H.C.:Zweifel,O. J A m . Chem. Soc. 1961,83,2544.

.,-."".

5. LipknvEtz,K. B.;Boyd,D. B . J . Chsm.Educ. 1982,69,269. 6. Ene1er.E. M.:Andae,J.D.:Schlcvor.P.v. R. J.Am. Chem Sor. 1973.95.8WS.

198%Appendix. R. A, J. Chem. Educ. 1989,66,836. 10. Simpson. J. M. J. Chom. Educ. 1989.66.106. 11. Lillie,T. S.:Yeegcr,K. J,Cham.Educ. 1989.66675. 1 2 U p k o w k K . J . Chem. Edve 1989,6,27S.
8. Bailey,

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