258 lines
11 KiB
TeX
258 lines
11 KiB
TeX
\documentclass[letterpaper]{article}
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\usepackage[T1]{fontenc}
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\usepackage{geometry}
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\geometry{margin = 1in}
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\usepackage{setspace}
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\usepackage{chemfig}
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\usepackage[style = chem-acs]{biblatex}
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\addbibresource{references.bib}
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\usepackage{graphicx}
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\usepackage{float}
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\newfloat{scheme}{htbp}{los}
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\floatname{scheme}{Scheme}
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\floatname{chart}{Chart}
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\newfloat{graph}{htbp}{loh}
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\usepackage{tabularx}
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\usepackage{chemformula} % Formulas using \ch{}
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% or
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\usepackage[version = 4]{mhchem} % Formulas using \ce{}
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\setcounter{secnumdepth}{-1}
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\newcommand*\mycommand[1]{\texttt{\emph{#1}}}
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\usepackage{authblk}
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\author[1]{Shivam Tripathi}
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\author[1]{Keshav Anand}
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\affil[1]{Plano East Senior High School, Plano, TX, United States}
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\title{Acid-Catalyzed Tandem Hydrolysis--Esterification of Acetylsalicylic Acid
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from Commerical Asprin Tablets to Form Methyl Salicylate}
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% Use the \date command for email address(s) of corresponding authors
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\begin{document}
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\maketitle
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\begin{abstract}
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Methyl salicylate was synthesized from commercial aspirin tablets via an acid-catalyzed
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tandem hydrolysis–esterification sequence. Acetylsalicylic acid (ASA) was extracted
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from the tablet matrix into methanol and reacted under reflux with a catalytic
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volume of \ce{H2SO4}. This one-pot method facilitates simultaneous deacetylation
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and Fischer esterification, bypassing the isolation of a salicylic acid intermediate.
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The resulting methyl salicylate was isolated via aqueous quenching and
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liquid--liquid extraction. Crude product purification was achieved through
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neutralization with saturated \ce{NaHCO3} and drying over anhydrous \ce{MgSO4}.
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This synthesis demonstrates an efficient, high-yield conversion of a common
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pharmaceutical precursor into a high-value fragrance ester, highlighting
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fundamental principles of equilibrium-driven organic transformations and
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multistep one-pot synthesis.
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\end{abstract}
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\section{Introduction}
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Acetylsalicylic acid (ASA), \ch{C9H8O4}, is a synthetic organic derivative of salicylic acid
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and is commonly known as aspirin~\cite{Fijakowski2022}.\\
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\begin{figure}[ht]
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\centering
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\vspace{1em} % Adds space above the molecule
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\chemfig{*6(-=-(-O-[:-30](=[:-90]O)-[:+30]CH_3)=([:60]-[:90](=[:150]O)-[:30]OH)-=)}
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\vspace{1em} % Adds space below the molecule
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\caption{Chemical structure of ASA}
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\label{fig:asa-structure}
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\end{figure}
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Commercial aspirin is commonly synthesized from salicylic acid through Eq~\ref{eq:aspirin-syn},
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and the two molecules differ by an ester group (\ch{-OCOCH3})~\cite{Sneader2000}.
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\begin{equation}
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\ce{C7H6O3 + C4H6O3 ->[H2SO4] C9H8O4 + CH3COOH}
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\label{eq:aspirin-syn}
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\end{equation} \\
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Another common derivative product of salicylic acid is methyl salicylate, \ch{C8H8O3}, commonly referred to
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as wintergreen oil. Methyl salicylate is commonly used in edibles (e.g. gum, mints), perfumes, and pain-relief
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ointments (e.g. Icy Hot, BenGay)~\cite{Guo2022}. Methyl salicylate also differs with salicylic acid by a single ester group and
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has simply been esterified differently than ASA.\\
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\begin{figure}[ht]
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\centering
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\vspace{1em} % Adds space above the molecule
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\chemfig{*6(-=-(-OH)=([:60]-[:90](=[:150]O)-[:30]O-[:+90]CH_3)-=)}
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\vspace{1em} % Adds space below the molecule
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\caption{Chemical structure of methyl salicylate}
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\label{fig:methyl-salicylate}
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\end{figure}
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Due to the similarity between the two molecules, ASA can be reacted to synthesize methyl salicylate~\cite{Hartel2009,nilered2017aspirin}.
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The purpose of this experiment was to convert acetylsalicylic acid obtained from
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commercial aspirin tablets into methyl salicylate through acid-catalyzed esterification
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in methanol under reflux conditions.
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\section{Results and discussion}
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\subsection {Extraction and Solvation of ASA}
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The synthesis began with the mechanical breakdown of commercial aspirin tablets (500~mg ASA/tablet) using a mortar and pestle. The resulting powder was digested in an excess of methanol for one hour with constant stirring. \\
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The heterogeneous mixture was subsequently clarified via filtration through a cellulose-based filter. This step effectively isolated the soluble ASA and miscible plasticizers from the insoluble structural excipients and pigments (Table~\ref{tbl:solubility}).
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\renewcommand{\arraystretch}{1.5} % Adds vertical space between rows
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\begin{table}[ht]
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\caption{Methanol Solubility/Miscibility Profile of Tablet Components}
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\label{tbl:solubility}
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\centering
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\begin{tabularx}{\textwidth}{l X l}
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\hline
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\textbf{Component Category} & \textbf{Specific Ingredients} & \textbf{Solubility in $\text{CH}_3\text{OH}$} \\
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\hline
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\textbf{Active Ingredient} & Acetylsalicylic Acid (ASA) & Soluble \\
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\textbf{Binders / Fillers} & Corn Starch, Powdered Cellulose & Insoluble \\
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\textbf{Coating Agents} & Carnauba Wax, Shellac, Hypromellose & Insoluble / Sparingly \\
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\textbf{Plasticizers} & Propylene Glycol, Triacetin & Miscible \\
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\textbf{Pigments / Lakes} & Titanium Dioxide, D\&C Red \#7, FD\&C Blue \#2, FD\&C Red \#40 & Insoluble \\
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\hline
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\end{tabularx}
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\end{table}
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\subsection{\ce{H2SO4} Catalyzed Tandem Hydrolysis--Esterification}
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The conversion of ASA to methyl salicylate proceeds via a one-pot tandem sequence (Scheme~\ref{sch:mechanism}). Concentrated \ce{H2SO4} serves as a Brønsted acid catalyst, activating the carbonyl groups toward nucleophilic attack by methanol, and as a dehydrating agent to shift the equilibrium.
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\begin{scheme}[H]
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\centering
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\small
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\setchemfig{atom sep=2.0em, compound sep=5em, nodesep=2pt}
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% Wrapper to ensure vertical alignment of the three main components
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\begin{tabular}{ccc}
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\chemname{
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\chemfig{*6(-=-(-O-[:-30](=[:-90]O)-[:+30]CH_3)=([:60]-[:90](=[:150]O)-[:30]OH)-=)}
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}{\footnotesize Acetylsalicylic Acid}
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&
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\parbox{2.5cm}{\centering $\xrightarrow[\Delta]{\ce{CH3OH, H2SO4}}$}
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&
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\chemname{
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\chemfig{*6(-=-(-OH)=([:60]-[:90](=[:150]O)-[:30]O-[:+90]CH_3)-=)}
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}{\footnotesize Methyl Salicylate}
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\end{tabular}
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\vspace{1.5em}
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\caption{Tandem deacetylation and Fischer esterification sequence.}
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\label{sch:mechanism}
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\end{scheme}
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The transformation encompasses two concurrent equilibrium-driven processes:
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\begin{enumerate}
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\item \textbf{Acid-Catalyzed Solvolysis:} The acetoxy group undergoes transesterification with methanol to yield salicylic acid and methyl acetate (Eq~\ref{eq:solvolysis}).
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\item \textbf{Fischer Esterification:} The carboxylic acid is esterified by the methanol solvent (Eq~\ref{eq:fischer}).
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\end{enumerate}
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\begin{equation}
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\ce{R-OCOCH3 + CH3OH <=>[H+] R-OH + CH3COOCH3}
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\label{eq:solvolysis}
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\end{equation}
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\begin{equation}
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\ce{Ar-COOH + CH3OH <=>[H+] Ar-COOCH3 + H2O}
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\label{eq:fischer}
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\end{equation}
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To drive the reaction toward the methyl salicylate product, a substantial stoichiometric excess of methanol was employed, utilizing Le Chatelier's principle to overcome the reversible nature of the esterification.
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\subsection{Kinetic and Thermodynamic Analysis}
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The transformation efficiency of the tandem hydrolysis--esterification is determined by the interplay between reaction rate and equilibrium position.
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\subsubsection{Thermal Activation and Collision Theory}
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The reflux duration is required to provide the activation energy ($E_{a}$) necessary for the nucleophilic attack on the sterically hindered aryl ester. According to the Arrhenius relationship, the rate constant $k$ increases exponentially with temperature:
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\begin{equation}
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k = Ae^{-E_{a}/RT}
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\end{equation}
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Operating at the boiling point of the solvent increases the frequency of effective collisions and facilitates the formation of the required carbocation intermediates.
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Furthermore, by employing a vast molar excess of methanol, the system effectively follows pseudo-first-order kinetics. Under these conditions, the concentration of the alcohol remains negligible in its variation, and the rate depends solely on the concentration of the limiting aspirin precursor:
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\begin{equation}
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-\frac{d[\text{ASA}]}{dt} = k'[\text{ASA}] \implies [\text{ASA}]_{t} = [\text{ASA}]_{0}e^{-k't}
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\end{equation}
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\subsubsection{Equilibrium Shifts and Chemical Potential}
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As a reversible process, the yield is limited by the equilibrium constant ($K$). Because the esterification step is endothermic ($\Delta H^\circ > 0$), the application of heat shifts the equilibrium toward the products. This temperature dependence is quantified by the Van't Hoff equation:
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\begin{equation}
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\frac{d \ln K}{dT} = \frac{\Delta H^\circ}{RT^{2}}
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\end{equation}
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The high reactant-to-substrate ratio further ensures that the reaction quotient ($Q$) remains lower than $K$ throughout the process. This maintains a negative Gibbs free energy ($\Delta G$), driving the reaction toward the formation of methyl salicylate:
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\begin{equation}
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\Delta G = \Delta G^\circ + RT \ln Q
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\end{equation}
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The combination of thermal input and stoichiometric bias effectively overcomes the reversible nature of the Fischer esterification.
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\subsection{Work-up and Purification}
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Following reflux, the reaction was quenched in ice-cold distilled water. Methyl salicylate ($\rho \approx 1.17$ g/mL) was isolated as the organic phase via liquid--liquid extraction. Residual acidic species (\ce{H2SO4}, \ce{CH3COOH}) were neutralized using saturated \ce{NaHCO3}:
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\begin{equation}
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\ce{H2SO4(aq) + 2NaHCO3(aq) -> Na2SO4(aq) + 2CO2(g) + 2H2O(l)}
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\end{equation}
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The organic extract was dried over anhydrous \ce{MgSO4} and filtered to yield the pure essential oil.
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\section{Experimental}
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\section*{Acknowledgements}
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Please use ``The authors thank \ldots'' rather than ``The authors would like to
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thank \ldots''.
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\section*{Supporting information}
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A listing of the contents of each file supplied as Supporting Information
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should be included. For instructions on what should be included in the
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Supporting Information as well as how to prepare this material for
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publications, refer to the journal's Instructions for Authors.
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The following files are available free of charge.
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\begin{itemize}
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\item Filename-1: brief description
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\item Filename-2: brief description
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\end{itemize}
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\printbibliography
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\newpage
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\rule{0.05in}{1.75in}%
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\sffamily
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\frenchspacing
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Some journals require a graphical entry for the Table of Contents. This
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\rule{0.05in}{1.75in}
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\end{document}
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