Penicillin Essay
The early twentieth century led to the discovery of penicillin, which revolutionized the use of curative agents to combat many bacterial contagions found around the globe. This was particularly useful in 1943 when the War Production Board outlined a plan to mass-produce a powdered formula of the drug to aid in the WWII American war effort.1 Penicillin’s use on Allied forces in the field reduced the number of amputations and deaths by an estimated 12-15%.2 Despite penicillin’s continued use today, uncertainties during the early-mid 1900’s regarding penicillin’s production costs and efficacy left a gap for research to find an alternative solution. Filling this opening, sulfa drugs quickly climbed to the top of research and development agendas of many major pharmaceutical companies.1 Sulfa drugs are any number of synthetically produced antibiotics that contain
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the molecular structure sulfanilamide.3 First prepared by Paul Gelmo in 1908 as part of a doctoral dissertation, sulfanilamide was patented just a year later. It was not until February of 1935 that Gerhard Domagk discovered sulfanilamide’s active form, which was made available to doctors for treatment only weeks later.4 Within months, feared diseases such as pneumonia, streptococcal infections, meningitis, gonorrhea, dysentery, and urinary tract infections were being managed at a rate that allowed research and development of major international pharmaceutical companies to boom. Sulfa drugs also led to the passage of the Federal Food, Drug, and Cosmetic Act of 1938 in the United States when insufficient testing led to at least 100 cases of diethylene glycol poisoning in 1937 due to tainted elixir sulfanilamide.5 Sulfa drugs not only brought a measure of chemotherapeutic control to bacterial infection management, but also lined the path for the molecular development of new drugs and pharmaceutical classes that targeted many non-communicable diseases as well.4 Sulfanilamide, also known as p-Aminebenzenesulfonamide, is the key component of sulfa drugs and is an organic compound composed of an aniline derived along with a sulfonamide group.6 Sulfanilamide acts by competitively inhibiting enzymatic reactions that involve para-aminobenzoic acid (PABA), which is needed in enzymatic reactions that produce folic acid and subsequent purine and pyrimidine synthesis.
Since mammals do not synthesize their own folic acid, PABA inhibitors such as sulfanilamide selectively kill bacteria without injuring the host (Figure 1). One of the most well-known preparation techniques of sulfanilamide is achieved by treating aniline with excess chlorosulfonic acid via replacement of hydrogen with a sulfonyl chloride group. This reagent forms sulfonic acid first before being converted into a sulfonyl chloride by the excess chlorosulfonic acid (Scheme 1). A key method of sulfanilamide production via this chlorosulfonic acid is the synthesis of p-acetaminobenzenesulfonyl chloride (P-ASC), in which a large quantity of sulfonic acid is required. This can pose serious environmental
problems. To alleviate this issue, another method of p-acetaminobenzenesulfonyl chloride formation can be used by substituting sulfonic acid with PCl5 as the chlorinating agent.7 Using this method has been shown to reduce the molar ratio of the raw product from 4.96 to 2.1 using CCl4 as the diluent (Scheme 2 & 3). Adding a small amount of NH4Cl also has been shown to dramatically increase sulfanilamide yield.7
Methods In this experiment, aniline reacts with trifluoroacetic anhydride (TFAA) to produce 2,2,2-trifluoroacetic anhydride (Scheme 4). Reactivity is greater in the case of the 2,2,2-trifluoroacetic anhydride, over the use of acetic anhydride, due to the electronegativity of the fluorine addition. This causes an inductive effect, causing the protons to be more acidic, thus allowing for a greater reactivity with aniline. Its addition in the first step is to act as an activating, ortho-/para-directing group for the chlorosulfonic anhydride addition. With this addition, the reactive amino group in aniline avoids protonation by the chlorosulfonic acid, which would make it a meta-directing group as opposed to para-. By using the amide instead of the free amine, nitrogen’s nucleophilic properties get reduced by resonance stabilization. The majority of the amide group in the acetanilide favors the para-substitution over ortho- due to steric hindrance.
Two equivalents of chlorosulfonic acid are added to the acetanilide via electrophilic aromatic substitution to generate 4-[trifluoroacetyl)amino]benzenesulfonyl chloride (Schemes 4 & 5). Both equivalents are necessary because they react with each other to form a dimeric chlorosulfonic anhydride. The anhydride acts as an electrophilic reagent in the electrophilic aromatic substitution reaction with acetanilide, forming the para-substitution of sulfonyl chloride.
The 4-[(trifluoroacetyl)amino]benzenesulfonyl chloride reacts with ammonia by breaking the S=O bond. The hydrogen coming off of the nitrogen atom is transferred to the negatively charged oxygen. A double bond is formed with oxygen, kicking HCl off to generate 2,2,2-trifluoro-N-(4-sulfamolyphenyl)acetamide (Scheme 6). The amide group hydrolyzes and water attacks the activated amide carbonyl carbon to generate a tetrahedral intermediate, which transfers a proton from the oxygen to the nitrogen. The amino group is removed to produce sulfanilamide and trifluoroacetic acid (Scheme 7).
Experimental
A solution of aniline (__ mL, 2.50 mmol) and CH2Cl2 (0.5 mL) was added to a solution of trifluoroacetic anhydride (TFAA, __ mL, 3.54 mmol) by syringe and let stir for 10 min. The reaction mixture was concentrated by evaporation to provide a crude 2,2,2-trifluoroacetanilide intermediate. The 2,2,2-trifluoroacetanilide intermediate and stir bar were transferred to a 5-10 mL round-bottom flask and attached to a reflex condenser. Added to the flask by pipet was chlorosulfonic acid (__ mL, 13.7 mmol), which was heated to 60-70 oC for 10 min. The reaction mixture was cooled to ambient temperature and placed in an ice-water bath. The cold reaction mixture was slowly added to crushed ice (__ mL) by pipet. The precipitate was collected via vacuum filtration and washed with ice-cold water (3 x 1 mL). The 4-[(trifluoroacetyl)amino]benzenesulfonyl chloride intermediate was allowed to air dry as a white/tan powder with a melting point of 142-144 oC. Its mass was determined to be 0.3514 g, giving a percent yield of ____.
the molecular structure sulfanilamide.3 First prepared by Paul Gelmo in 1908 as part of a doctoral dissertation, sulfanilamide was patented just a year later. It was not until February of 1935 that Gerhard Domagk discovered sulfanilamide’s active form, which was made available to doctors for treatment only weeks later.4 Within months, feared diseases such as pneumonia, streptococcal infections, meningitis, gonorrhea, dysentery, and urinary tract infections were being managed at a rate that allowed research and development of major international pharmaceutical companies to boom. Sulfa drugs also led to the passage of the Federal Food, Drug, and Cosmetic Act of 1938 in the United States when insufficient testing led to at least 100 cases of diethylene glycol poisoning in 1937 due to tainted elixir sulfanilamide.5 Sulfa drugs not only brought a measure of chemotherapeutic control to bacterial infection management, but also lined the path for the molecular development of new drugs and pharmaceutical classes that targeted many non-communicable diseases as well.4 Sulfanilamide, also known as p-Aminebenzenesulfonamide, is the key component of sulfa drugs and is an organic compound composed of an aniline derived along with a sulfonamide group.6 Sulfanilamide acts by competitively inhibiting enzymatic reactions that involve para-aminobenzoic acid (PABA), which is needed in enzymatic reactions that produce folic acid and subsequent purine and pyrimidine synthesis.
Since mammals do not synthesize their own folic acid, PABA inhibitors such as sulfanilamide selectively kill bacteria without injuring the host (Figure 1). One of the most well-known preparation techniques of sulfanilamide is achieved by treating aniline with excess chlorosulfonic acid via replacement of hydrogen with a sulfonyl chloride group. This reagent forms sulfonic acid first before being converted into a sulfonyl chloride by the excess chlorosulfonic acid (Scheme 1). A key method of sulfanilamide production via this chlorosulfonic acid is the synthesis of p-acetaminobenzenesulfonyl chloride (P-ASC), in which a large quantity of sulfonic acid is required. This can pose serious environmental
problems. To alleviate this issue, another method of p-acetaminobenzenesulfonyl chloride formation can be used by substituting sulfonic acid with PCl5 as the chlorinating agent.7 Using this method has been shown to reduce the molar ratio of the raw product from 4.96 to 2.1 using CCl4 as the diluent (Scheme 2 & 3). Adding a small amount of NH4Cl also has been shown to dramatically increase sulfanilamide yield.7
Methods In this experiment, aniline reacts with trifluoroacetic anhydride (TFAA) to produce 2,2,2-trifluoroacetic anhydride (Scheme 4). Reactivity is greater in the case of the 2,2,2-trifluoroacetic anhydride, over the use of acetic anhydride, due to the electronegativity of the fluorine addition. This causes an inductive effect, causing the protons to be more acidic, thus allowing for a greater reactivity with aniline. Its addition in the first step is to act as an activating, ortho-/para-directing group for the chlorosulfonic anhydride addition. With this addition, the reactive amino group in aniline avoids protonation by the chlorosulfonic acid, which would make it a meta-directing group as opposed to para-. By using the amide instead of the free amine, nitrogen’s nucleophilic properties get reduced by resonance stabilization. The majority of the amide group in the acetanilide favors the para-substitution over ortho- due to steric hindrance.
Two equivalents of chlorosulfonic acid are added to the acetanilide via electrophilic aromatic substitution to generate 4-[trifluoroacetyl)amino]benzenesulfonyl chloride (Schemes 4 & 5). Both equivalents are necessary because they react with each other to form a dimeric chlorosulfonic anhydride. The anhydride acts as an electrophilic reagent in the electrophilic aromatic substitution reaction with acetanilide, forming the para-substitution of sulfonyl chloride.
The 4-[(trifluoroacetyl)amino]benzenesulfonyl chloride reacts with ammonia by breaking the S=O bond. The hydrogen coming off of the nitrogen atom is transferred to the negatively charged oxygen. A double bond is formed with oxygen, kicking HCl off to generate 2,2,2-trifluoro-N-(4-sulfamolyphenyl)acetamide (Scheme 6). The amide group hydrolyzes and water attacks the activated amide carbonyl carbon to generate a tetrahedral intermediate, which transfers a proton from the oxygen to the nitrogen. The amino group is removed to produce sulfanilamide and trifluoroacetic acid (Scheme 7).
Experimental
A solution of aniline (__ mL, 2.50 mmol) and CH2Cl2 (0.5 mL) was added to a solution of trifluoroacetic anhydride (TFAA, __ mL, 3.54 mmol) by syringe and let stir for 10 min. The reaction mixture was concentrated by evaporation to provide a crude 2,2,2-trifluoroacetanilide intermediate. The 2,2,2-trifluoroacetanilide intermediate and stir bar were transferred to a 5-10 mL round-bottom flask and attached to a reflex condenser. Added to the flask by pipet was chlorosulfonic acid (__ mL, 13.7 mmol), which was heated to 60-70 oC for 10 min. The reaction mixture was cooled to ambient temperature and placed in an ice-water bath. The cold reaction mixture was slowly added to crushed ice (__ mL) by pipet. The precipitate was collected via vacuum filtration and washed with ice-cold water (3 x 1 mL). The 4-[(trifluoroacetyl)amino]benzenesulfonyl chloride intermediate was allowed to air dry as a white/tan powder with a melting point of 142-144 oC. Its mass was determined to be 0.3514 g, giving a percent yield of ____.