In the Laboratory
Synthesis and Spectroscopic Analysis of a Cyclic Acetal: A Dehydration Performed in Aqueous Solution
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David M. Collard,* Adolphus G. Jones, and Robert M. Kriegel School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400; *
[email protected] The mechanism for the formation of ketals (and acetals) and their use as protecting groups for ketones (and aldehydes) appears in most introductory organic chemistry textbooks. These functional groups, along with hemiacetals and hemiketals, play important roles in biological chemistry; for example, α-D-glucose, 1, is a hemiacetal formed by intramolecular reaction of an alcohol and aldehyde; multistriatin, 2, a pheromone of the European elm bark beetle (1), is a bicyclic ketal formed by intramolecular reaction of a diol and a ketone. CH2OH O H
HO HO HO
Experimental Procedure
O O
OH
1
2
Cyclic ketals are formed by the acid-catalyzed reaction of a ketone and a diol (e.g., ethylene glycol, Scheme I). Current organic chemistry laboratory texts include few procedures for the synthesis of ketals or acetals (2). O
+ R
R'
H+
HO
OH
O
O
R
R'
+ H2O
Scheme I
The formation of acetals and ketals is a dehydration; water is condensed from the starting materials. It is an equilibrium reaction and is usually performed in nonaqueous media with removal of water from the reaction mixture. Treatment of acetals and ketals with aqueous acid results in a hydrolysis reaction with the liberation of the carbonyl compound (aldehyde or ketone) and the diol. Here we present an experiment in which two hydroxyl groups of a tetra-alcohol, pentaerythritol, react with benzaldehyde in the presence of acid to form a benzal, 5,5bis(hydroxymethyl)-2-phenyl-1,3-dioxiane (an acetal derived from benzaldehyde) (Scheme II). The remaining hydroxyl groups remain unreacted. This reaction has a number of interesting features: (i) the isolated product is the monobenzal, 3, not the dibenzal, 4; (ii) the reaction is performed in water; and (iii) the product contains nonequivalent geminal protons, which are apparent only when the three-dimensional structure of 3 is considered. O
HO
OH
+
Ph H
HO
H+ H2O
O
OH
+ H2O
Ph O
OH
OH
3 Scheme II
The reaction of benzaldehyde and pentaerythritol can be performed on either microscale or macroscale. The experiment uses water as the solvent, and the starting materials are 70
inexpensive and nontoxic. The procedure is straightforward and suitable for incorporation into an introductory organic laboratory course as an exercise in one 3-hour period. It illustrates a number of important concepts from the organic chemistry curriculum (synthesis, equilibrium), it presents an interesting analysis of inequivalent protons by NMR spectroscopy (3), and it serves as the basis for introduction of more advanced concepts. Alternatively, it can serve as a group exercise in optimizing the conditions of a reaction to maximize the yield of the desired product
Pentaerythritol (1.8 g, 13 mmol) and 26 mL of water are placed in a 50-mL round-bottom flask or Erlenmeyer flask equipped with a magnetic stir bar and a thermometer. The solid is dissolved by gently heating the mixture to 35 °C in a water bath on a hot-plate/stirrer. Upon dissolution of pentaerythritol, concentrated hydrochloric acid (2 drops, ca. 0.1 mL) is added, followed by benzaldehyde (1.4 mL, 14 mmol). The temperature is maintained at 35 °C for one hour, during which a solid precipitates. The mixture is filtered, and the solid is washed with 1 mL of cold water and air-dried in the filter. Recrystallization of the solid from ca. 12 mL of toluene gives 5,5-bis(hydroxymethyl)-2-phenyl-1,3-dioxane, 3, as a colorless solid, which is air-dried on the filter. Students should record the melting point and the 1H NMR spectrum of the crude (filtered) solid and the recrystallized product. Recrystallized 5,5-bis(hydroxymethyl)-2-phenyl-1,3-dioxane gives a melting point of 135–137 °C (lit. 134–135 °C [4 ]). The 1H NMR (300 MHz, DMSO-d6; see below for discussion of the peak assignment) has peaks at δ 3.22 (d, JHCOH = 5 Hz, 2H, axial exocyclic CH2), δ 3.70 (d, JHCOH = 5 Hz, 2H, equatorial exocyclic CH2), δ 3.80 (d, Jgem = 12 Hz, 2H, C4,6 axial H), δ 3.90 (d, Jgem = 12 Hz, 2H, C4,6 equatorial H), δ 4.55 (t, JHOCH = 5 Hz, 1H, axial OH), δ 4.62 (t, JHOCH = 5 Hz, 1H, equatorial OH), δ 5.40 (s, 1H, benzylic H), 7.40– 7.55 (multiplet, 5H, aryl H). 13C NMR (75 MHz, DMSOd6): δ 139, 129, 128, 126 (aromatic C); δ 100 (C2), 69 (C4,6), 61, 59 (exocyclic CH2); IR (KBr): 3289 cm᎑1 (OH str.), 1453 (aromatic C–C), 1038 (C–O str.). Hazards Care should be taken when handling concentrated hydrochloric acid. Results and Discussion
Observations and Reaction Optimization Reaction of pentaerythritol with benzaldehyde in aqueous acid gives 5,5-bis(hydroxymethyl)-2-phenyl-1,3-dioxane, 3.
Journal of Chemical Education • Vol. 78 No. 1 January 2001 • JChemEd.chem.wisc.edu
In the Laboratory
Although this is an equilibrium dehydration reaction, the reaction proceeds in water owing to the insolubility of the product in the aqueous reaction medium. This has two important consequences: (i) the product of the equilibrium is removed from the reaction mixture, driving the reaction to completion, and (ii) the remaining hydroxyl groups do not undergo reaction with a second equivalent of benzaldehyde to form the dibenzal. Although this is an equilibrium reaction (Scheme II) that should be driven to the left by the presence of water, the reaction proceeds to give the benzal 3. Clearly, formation and isolation of product proceed by formation of a small concentration of benzal at equilibrium, which is removed from solution (and the equilibrium) by precipitation. The reaction is quite sensitive to temperature. Below 35 °C, pentaerythritol precipitates from the mixture, effectively removing it from the reaction. On the other hand, raising the temperature above 35 °C leads to formation of more of the dibenzal. The 1H NMR spectrum of the crude product isolated by filtration shows the peaks of the product and the dibenzal 4 (which can be prepared separately if desired) (see below). The relative amount of monobenzal (3) and dibenzal (4) is best assessed by integration of the two methine singlets at δ 5.40 and 5.50 ppm, respectively. A single recrystallization of the filtered solid from toluene effectively separates the monobenzal from the dibenzal. Pentaerythritol gives peaks in the 1H NMR spectrum (obtained in DMSO-d6) at δ 3.36 (t, J = 7 Hz, 4H, OH), δ 4.21 (d, J = 7 Hz, 8H, CH2). Any unreacted pentaerythritol in the crude product is not removed in the recrystallization from toluene. Thus, it is important that the mixture is at 35 °C at the end of the reaction to keep any unreacted pentaerythritol in solution so that it is not filtered off with the product. If pentaerythritol is present in the product, a second recrystallization from 5% aqueous Na2CO3 is required to provide pure 3.
The experiment can be used as an exercise to illustrate optimization of reaction conditions to maximize the yield of a desired product by having groups of students perform the synthesis at different temperatures or with different reaction times and reagent concentrations. For example, a plot of the molar ratio of unreacted pentaerythritol, desired product 3, and dibenzal 4 (determined by 1H NMR of the filtered solid), is shown in Figure 1. At low temperature, pentaerythritol does not dissolve and is recovered from the mixture by filtration. At high temperature, the relative amount of dibenzal increases. 1H
NMR Spectroscopy of 5,5-Bis(hydroxymethyl)-2phenyl-1,3-dioxane, 3 The proton NMR spectrum of 3 in deuterated dimethylsulfoxide, DMSO-d6, shows a number of interesting features (Fig. 2, top).1 The peak at δ 7.4–7.5 corresponding to five protons (peak a) is assigned to the phenyl protons, and the one-proton singlet at δ 5.40 (peak b) is assigned to the proton on C-2. The remainder of the spectrum consists of two triplets with a small coupling constant (δ 4.62 and 4.55, peaks c and d, J = 5 Hz), a pair of doublets with large coupling constants, each accounting for two protons (δ 3.90 and 3.80, peaks e and f, J = 12 Hz), and two two-proton doublets (δ 3.70 and 3.22, peaks g and h, J = 5 Hz). Assignment of the proton
1.0
pentaerythritol
dibenzal, 4
mole ratio
0.8
0.6
0.4
monobenzal, 3 0.2
0.0 0
10
20
30
40
50
60
70
Temperature / °C Figure 1. Plot of molar ratio of unreacted pentaerythritol, desired product (3), and dibenzal (4) in crude filtered product as a function of reaction temperature. The molar ratios were determined by comparison of the integrals of 1H NMR peaks at δ 4.21 (for pentraerythritol, integral divided by 8 to account for the relative number of protons), δ 5.40 (one proton of 3), and δ 5.50 (for 4, integral divided by 2). For reactions above 35 °C, the reaction mixture is cooled briefly to 35 °C before filtration (this precipitates more solid while keeping any unreacted pentaerythritol in solution).
Figure 2. Top: Three-dimensional structure and 1H NMR of 5,5bis(hydroxymethyl)-2-phenyl-1,3-dioxane (3) in DMSO-d6 (300 MHz). Bottom: Three-dimensional structure of 4, with phenyl rings occupying equatorial positions on each ring, identifying pairs of identical protons (Ha , Hb , Hc , and Hd ); and 1H NMR (DMSO-d6, 300 MHz). The peak for water is marked with a star.
JChemEd.chem.wisc.edu • Vol. 78 No. 1 January 2001 • Journal of Chemical Education
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In the Laboratory
spectra is aided by homonuclear decoupling of individual peaks or a COSY experiment, although these techniques are not necessary for complete structural determination. Protons that give rise to peaks e and f couple each other, as shown by the common 12-Hz coupling constant. Each of the doublets with a 5-Hz coupling constant (peaks g and h) couples to one of the triplets (peaks c and d, respectively) and not to the other doublet. Interpretation of this spectrum requires that students recognize the three-dimensional nature of the molecule. The dioxane ring adopts a chair conformation similar to a cyclohexane ring, as shown in Figure 2 (top), with the bulky phenyl group occupying an equatorial position. With the ring locked in this conformation, the hydroxymethyl group on C-5 trans to the phenyl ring occupies an equatorial position, and the cis hydroxymethyl group is in an axial position. Thus, these groups are inequivalent and give different signals in the 1H NMR spectrum. The two protons on C-4 (and C-6) are nonequivalent (i.e., equatorial and axial, cis and trans to the phenyl substituent) and display geminal coupling ( J = 12 Hz). Exact assignment of signals to a particular position (axial or equatorial) is probably beyond the scope of an introductory course. However, this can be a good point to address deshielding cones associated with σ-bonds, which are often introduced in advanced organic structure determination textbooks (5). The equatorial protons of the dioxane ring appear further downfield than the axial protons, and the protons of the equatorial exocyclic methylene group appear further downfield than those of the axial exocyclic methylene group. The hydroxyl protons appear as triplets owing to coupling to the two protons of the attached exocyclic methylene (i.e., H–O–C–H). The 1H NMR spectra of alcohols in CDCl3 usually give broad singlets for the hydroxyl group owing to fast proton exchange. However, this exchange is slower in DMSOd6 and the protons reside on the oxygen long enough to experience coupling to the protons on the adjacent carbon (6 ).
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Acknowledgments We thank the National Science Foundation for the support of educational initiatives through the presentation of a CAREER Award (to DMC) and funds for the purchase of the NMR spectrometer through the ILI program. W
Supplemental Material
The written material given to students, notes for the instructor, and CAS registry numbers for all chemicals are available in this issue of JCE Online. Note 1. Because 3 is insoluble in chloroform, CDCl3 cannot be used as a solvent for the NMR analysis. In DMSO-d6, additional peaks appear at δ 2.50 (proton impurity in DMSO) and δ 3.44 (water in DMSO; this peak is split into a doublet in the presence of 3 or 4 owing to hydrogen bonding).
Literature Cited 1. Brown, W. H.; Foote, C. S. Organic Chemistry, 2nd ed.; Saunders: Fort Worth, TX, 1998; p 587. 2. Williamson, K. L. Macroscale and Microscale Organic Experiments, 3rd ed.; Houghton Mifflin: Boston, 1999; p 627. 3. Rowland, A. T. J. Chem. Educ. 1983, 60, 1084. Rablen, P. R.; Deuber, M. A.; Lim, A. C; Dickson, R. M.; Wintner, C. E. J. Chem. Educ. 1991, 68, 796. 4. Bograchov, E. J. Am. Chem. Soc. 1950, 72, 2268. Issidorides, C. H.; Gulen, R. Org. Synth. Coll. Vol. IV, 1963, 679. 5. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identification of Organic Compounds, 5th ed.; Wiley: New York, 1991; p 175. 6. Chapman, O. L.; King, R. W. J. Am. Chem. Soc. 1964, 86, 1256.
Journal of Chemical Education • Vol. 78 No. 1 January 2001 • JChemEd.chem.wisc.edu
