Running an Organic Reaction

Introduction

In our discussion of host-guest chemistry, the structure shown in Figure 1 was offered as a target molecule for the synthesis of a compound that would mimic the catalytic acitivity of the enzyme carboxypeptidase.

Figure 1

A Potential Enzyme Mimic

Attempts to synthesize the target molecule involved the reaction shown in Equation 1

Exercise 2 Identify the role (i.e. reagent, catalyst, or solvent) of each of the compounds shown above the arrow in Equation 1. t-BuSi(CH₃)₂Cl = imidazole = DMF =

2,6-Bis(t-butyldimethylsilyloxy)-4'-bromo-3'-methoxymethoxymethy-1,1'-biphenyl (13). By a modified procedure¹⁶, a soln of 3.43 g (9.35 mmol) of diol 27¹ and 3.82 g (56.1 mmol) of imidazole² in 25 mL of anhyd DMF³ (dried with 3 Å molecular sieves) was cooled in ice⁴ under argon⁵ and 4.23g (28.0 mmol) of t-butyldimethylsilyl chloride¹ was added. The yellow soln was stirred at 25^o for 1 day⁶, and diluted with ether⁷. The soln was washed three times with water⁸, once with brine⁹, and the solvent was evaporated (vacuum) to give 6.2 g of oil. This material was filtered through 60 g of SiO₂ (25% CH₂Cl₂-hexane; 6-8 c.v.)¹⁰ to give 3.54 g (64%) of 13, m.p. 61-62^{o 11}; ¹H-NMR¹² d 7.619 (d, 1H, J=2.1 Hz, ArH), 7.538-7.438 (A₂B, 3H, J=7.9 Hz, ArH), 7.354 (d, 1H, J=2.1 Hz, ArH), 7.015 (dd, 1H, J=8.1, 2.1 Hz, ArH), 4.769 (s, 2H), 4.729 (s, 2H), 4.387 (s, 4H, ArCH₂OSi), 3.430 (s, 3H, OCH₃), 0.912 (s, 18H, CH₃C), 0.007 (s, 12H, CH₃Si); MS¹³ exact mass calc for C₂₅H₃₈BrO₄Si₂ (M⁺-t-Bu) 539.1396 and 537.1492; found m/e 539.1384 and 537.1471. (Found:¹⁴ C, 58.52; H, 7.78; Br, 13.44; Si, 9.35. Calc for C₂₅H₃₈BrO₄Si₂: C, 58.47; H, 7.95; Br, 13.41; Si, 9.43%.)

Preliminary Planning ¹ The molar ratio of t-butyldimethylsilyl chloride to 27 is 3/1. Since there are two OH groups in 27, the experimentalist decided in the preliminary planning stage to use 1.5 mmol of t-butyldimethylsilyl chloride per OH group. It is common to use an excess of reagent in order to insure complete conversion of the reactant to product. This avoids the problem of having to get rid of unreacted starting material.

² The imidazole serves two roles in this reaction. First, it reacts with the t-butyldimethylsilyl chloride to form an "activated" form of this compound. Second, it acts as a base to react with the HCl that is formed as a side product in the reaction. The 2/1 ratio of imidazole to t-butyldimethylsilyl chloride reflects the dual role that the imidazole plays in the reaction.

³ The solvent for the reaction was anhydrous dimethyl formamide, a dipolar aprotic solvent. Previous experience may have dictated this choice. It was dried because t-butyldimethylsilyl chloride reacts rapidly with moisture.

Running the Reaction ⁵The reaction was performed under an atmosphere of argon because the t-butlydimethysilyl chloride reacts with atmospheric oxygen and moisture.

⁴ It was run at 0^o initially because the reaction is very exothermic. Keeping the temperature low reduces the likelihood of undesired side products.

⁶ After the initial exothermic reaction subsided, the guy went home. The ice melted and the temperature had risen to 25^o by the time he came back the next morning to work-up the reaction.

The Work-Up ⁷Since DMF is miscible with water, ether was added in order to create a 2-phase system. This facilitated extraction of the product.

⁸ Washing with water removed most of the DMF. It also destroyed the excess t-butyldimethylsilyl chloride.

⁹ Washing with brine (saturated NaCl solution) is a standard method of removing small amounts of water from an imiscible solvent such as ether.

¹⁰ Evaporation removed the ether and left a crude product which was purified by filtering through silica gel (SiO₂). This is essentially a chromatographic purification. It probably separated left over imidazole as well as any compounds formed by treating t-butyldimethylsilyl chloride with water.

Product Analysis and Identification ¹¹The melting point is a standard physical property.

¹² This is a summary of the proton NMR spectrum.

¹³ This is a the most important mass spectal data. It compares theoretical and experimental values. Note how close to the theoretical values the experimental values are. This gives you confidence that you have made the compound you claim to have made.

¹⁴ These are the results of elemental analysis. Again, the experimental values are compared to the expected values.

Chemical Reactions

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