The intermediate oxidation state of carbon in carbonyl compounds specifies its ability to take part — Organic Chemistry Chemistry Question
Synthesis of 4-(4-methylphenyl)-4-hydroxybutanoic acid
The intermediate oxidation state of carbon in carbonyl compounds specifies its ability to take part in oxidation-reduction reactions. Depending on the selected reaction conditions the reduction of a carbonyl group can lead either to alcohols (primary in the case of aldehydes and secondary in the case of ketones) or saturated hydrocarbons. The latter are typically formed as a result of hydrogenation at elevated temperature and high pressure, still can also be obtained under relatively mild conditions (e.g. via Clemmensen or Wolff-Kischner reactions).
Reduction of carbonyl compounds to alcohols can be successfully carried out by catalytic hydrogenation. Still, the preference is nowadays given to other chemical processes due to the simplicity of experimental procedures and accessibility of reagents.
Hydride complexes of aluminum (or boron) and alkaline metals are indispensable in organic synthesis due to their high reducing ability in a wide range of temperatures and the possibility of choosing appropriate complexes applicable in solvents with different polarity. In this task you will get acquainted with one of such reagents, sodium borohydride.
[VISUAL]
Chemicals and reagents
* β-(4-methylbenzoyl)-propionic acid, 4 g,
* Sodium borohydride, 0.8 g,
* Sodium hydroxide, 2.5 mol dm-3 aqueous solution, 24 cm3,
* Hydrochloric acid, 6 mol dm-3 aqueous solution, 20 cm3,
* Distilled water, 100 cm3.
Equipment and glassware
* Laboratory stand with clamps,
* Three-necked flask, 250 cm3,
* Reflux condenser with breather tube,
* Dropping funnel, 100 cm3,
* Magnetic stirrer with heating,
* Teflon magnetic stir bar,
* Hoses,
* Thermometer with a tapered joint,
* Tapered joint stopper,
* Ice bath,
* Beaker, 100 cm3 (2 ea.),
* pH indicator paper,
* Fritted glass filter, porosity 2 – 3,
* Glass rod,
* Melting point apparatus,
* Capillary for melting point determination (2-3 ea.),
* Glass tube for capillary filling,
* Spatula,
* Teflon sleeves for tapered joints or vacuum grease,
* Analytical balances (± 0.001 g)
Procedure
A. Assembly of the apparatus
Assemble the apparatus as shown in the picture in Problem 30. Equip every joint with the Teflon sleeve or apply vacuum grease.
B. Preparation of the reagents and synthesis of the product
Prepare the solution of 0.8 g of sodium borohydride in 12 cm3 of water and pre-cool it to 0 – 5 °C. Fix the three-necked flask at the laboratory stand over the magnetic stirrer. Weigh out and admeasure the required amounts of the reagents. Place 4 g of β-(4-methylbenzoyl)-propionic acid and 12 cm3 of 2.5 mol dm-3 aqueous solution of NaOH in the flask and equip it with the reflux condenser with a breather tube, the dropping funnel and the stir bar. Switch on stirring. Fix the unused neck with the thermometer so that its tip is submerged into the reaction mixture. Place the ice-water bath under the flask. When the reaction mixture gets cooled down to 0 – 5 °C, quickly add with intensive stirring the pre-cooled sodium borohydride solution. Remove the ice-bath and let the reaction mixture warm up to room temperature. Gently heat up the mixture to boiling and keep refluxing for 40 min. Then add 12 cm3 of 2.5 mol dm-3 aqueous solution of NaOH to the heated reaction mixture and continue refluxing for another 20 min.
C. Isolation of the product
Switch off the heating. Cool the flask down to room temperature and then place it in the ice-water bath containing sodium chloride. Fill the dropping funnel with 15 cm3 of HCl solution (6 mol dm-3) and add the acid solution slowly to the flask under vigorous stirring continuously monitoring the pH of the reaction mixture with the pH indicator paper (capture a drop of the reaction mixture with the glass rod through the neck of the flask and apply it to the test paper). Important! The temperature of the reaction mixture must not exceed 5 °C. Instantly control the temperature keeping the tip of the thermometer submerged into the reaction mixture. Adjust the pH to 2 and observe precipitation of white crystals. Filter out the product using the fritted glass filter and wash it 2-4 times with ice-cold water until the pH of the filtrate attains 4 - 5. Air-dry the resulting white precipitate on a filter paper for a few hours. To accelerate the process the precipitate may be placed in a round-bottom flask and dried out on a rotary evaporator under reduced pressure. Control the dryness of the product by determining its melting point.
Place the non-sealed end of the capillary into the product crystals, then turn it the sealed end down and throw several times down through a longer glass tube. Check that the sealed end side of the capillary is filled with the product. Apply the ready capillary to the melting point apparatus and record the melting point of the product. Compare the value with the reference data and draw a conclusion about the product purity.
D. Analysis of the product
Weigh the product. Calculate the yield.
What effects does an alkali produce on the starting materials and the reaction intermediates? Write down the equation of sodium borohydride reaction with water in neutral medium. Suggest the mechanism of the lactone disruption.
Model Answer
Product Appearance: White crystals
Melting/Boiling point, °C: 97 - 99 °C
Yield, %: 3.0 g (72%)
NMR reference data (CDCl3)
2.07 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.48 (t, 2H, J=7.3 Hz, CH2), 4.75 (t, 2H, J=7.3 Hz, CHOH), 7.17 (d, 2H, 2H, J=8.0 Hz), 7.24 (d, 2H, 2H, J=8.0 Hz) [ArH]
Solution:
Transformation of the acid in readily soluble anionic form is the main reason behind carrying out the reaction in alkaline medium (the protonated acid is practically insoluble in water). Also, sodium borohydride is stable in alkaline medium, whereas it undergoes decomposition with hydrogen evolution in neutral and especially in acidic medium. In neutral medium, the reaction equation is written down as:
NaBH4 + 4 H2O → Na[B(OH)4] + 4 H2
The mechanism of the lactone disruption is as follows:
[VISUAL]
Why does addition of the acid at the final stage of the synthesis lead to the product precipitation?
Model Answer
4-(4-Methylphenyl-4-hydroxybutanoic acid is a weak acid. Its solubility in water in the non-dissociated form is low. By contrast, the solubility of the anionic form is considerably higher, since its negative charge effectively interacts with the solvent. The anionic form predominates in the alkaline medium. Addition of a strong acid leads to the carboxylate protonation, and the non-dissociated acid precipitates.
Consider an alkylaldehyde and a dialkyl ketone. Which carbonyl group is more readily reduced with sodium borohydride? Justify your answer.
Model Answer
Readiness to reduction correlates with the value of the partial positive charge (δ+) on the carbon atom in the carbonyl group. Both alkyl groups in ketones produce the +I effect on the carbonyl carbon atom. At the same time, there is only one group of this type in aldehydes. Thus, the value of δ+ on the carbon atom is higher in the case of the aldehyde group, and it is more readily reduced with sodium borohydride.
The reaction considered in this Problem serves as an example of the selective reduction of a keto group in the presence of a carboxyl one. Propose a way how a carboxyl group can be selectively reduced in the presence a carbonyl group.
Model Answer
Reduction of a carboxyl group in the presence of a carbonyl one turns out to be a much more complicated task. The carbonyl group should be first protected, e.g. by the formation of a cyclic acetal as a result of the reaction with ethylene glycol in acidic medium. Then a strong reagent (e.g. lithium aluminum hydride) is applied to reduce the carboxyl group. Finally, the protecting group is removed under mild acidic conditions.
[VISUAL]
A compound with the molecular formula C17H25NO2 is produced when the starting compound is treated with cyclohexylamine (in equimolar amount to ketoacid) in methanol in the presence of catalytic amounts of a strong acid followed by the addition of sodium borohydride. Suggest the structures of the final and intermediate products as well as the mechanism of the first stage of the reaction.
Model Answer
The combination of nucleophilic addition of an amine with subsequent reduction is referred to as reductive amination. The nucleophilic amine is attached to the carbonyl group affording the imine, which is further reduced to the amine with sodium borohydride.
The intermediate product:
[VISUAL] (Imine intermediate)
The final product:
[VISUAL] (Reductive amination amine product)
The reaction mechanism:
[VISUAL]