SMILES: C1=CC=C(C(=C1)C(=O)O)O
IUPAC name: 2-hydroxybenzoic acid

🧪 Chemical Profile: acetic anhydride

IUPAC Name: acetyl acetate
PubChem CID: 7918

📐 Computed Local Properties (RDKit)

Could not resolve a valid SMILES string for RDKit analysis.

🌡️ Experimental Properties (PubChem)

• Boiling Point: 283.19 °F at 760 mmHg (NTP, 1992)

⚠️ Experimental Hazards (PubChem)

• H226: Flammable liquid and vapor
• H290: May be corrosive to metals
• H302: Harmful if swallowed
• H313: May be harmful in contact with skin
• H314: Causes severe skin burns and eye damage
• H318: Causes serious eye damage
• H330: Fatal if inhaled
• H331: Toxic if inhaled
• H332: Harmful if inhaled
• H335: May cause respiratory irritation
• H336: May cause drowsiness or dizziness
• H370: Causes damage to organs
• H372: Causes damage to organs through prolonged or repeated exposure
• H402: Harmful to aquatic life

Molecule: CC(=O)OC(C)=O
Formula: C4H6O3
Exact mass: 102.0317 Da
Average molecular weight: 102.0890 g/mol

Invalid SMILES: 'C(=O)(C1=CC=CC=CC1=C(O)=O)O'

SMILES: C1=CC=C(C(=C1)C(=O)O)O
IUPAC name: 2-hydroxybenzoic acid

Molecule: O=C(O)c1ccccc1O
Formula: C7H6O3
Exact mass: 138.0317 Da
Average molecular weight: 138.1220 g/mol

⚖️ Stoichiometry Engine

Balanced Equation:
1.0 C4H6O3 + 11.0 C7H6O3 → 9.0 C9H8O4

Reactant Analysis:
- C4H6O3: Mass not provided, cannot calculate limit.
- C7H6O3: Provided 2.0g (MW: 138.12 g/mol) = 0.0145 moles.

Limiting Reactant: C7H6O3 (Supports 0.0013 theoretical reaction cycles)

Theoretical Yield (Products):
- C9H8O4: 0.0118 moles produced (2.13 g).

🧪 Chemical Profile: phosphoric acid

IUPAC Name: phosphoric acid
PubChem CID: 1004

📐 Computed Local Properties (RDKit)

Could not resolve a valid SMILES string for RDKit analysis.

🌡️ Experimental Properties (PubChem)

• Boiling Point: greater than 266 °F at 760 mmHg (USCG, 1999)

⚠️ Experimental Hazards (PubChem)

• H290: May be corrosive to metals
• H302: Harmful if swallowed
• H313: May be harmful in contact with skin
• H314: Causes severe skin burns and eye damage
• H318: Causes serious eye damage
• H331: Toxic if inhaled
• H332: Harmful if inhaled
• H335: May cause respiratory irritation
• H370: Causes damage to organs
• H402: Harmful to aquatic life

Research will be limited to:
- Reactants: Acetic Anhydride
- Reactants: Salicylic Acid
- Product: Aspirin
- Parameters: Temperature
- Parameters: Duration

Strategy: I will investigate the kinetics and yield optimization of the esterification reaction between salicylic acid and acetic anhydride. The goal is to identify the specific temperature ranges (typically 50-90°C) and reaction times (typically 10-30 minutes) that maximize yield while minimizing decomposition or byproduct formation. I will look for experimental studies and chemical engineering papers that provide quantitative data on these parameters.
Queries:
- aspirin synthesis salicylic acid acetic anhydride optimal temperature duration yield
- kinetics of esterification salicylic acid acetic anhydride temperature dependence
- optimization of acetylsalicylic acid synthesis reaction time temperature
- effect of temperature on aspirin yield and purity acetic anhydride method

Executing 4 concurrent searches:
- aspirin synthesis salicylic acid acetic anhydride optimal temperature duration yield
- kinetics of esterification salicylic acid acetic anhydride temperature dependence
- optimization of acetylsalicylic acid synthesis reaction time temperature
- effect of temperature on aspirin yield and purity acetic anhydride method

Found 5 papers. Key excerpts:

Controlled release from aspirin based linear biodegradable poly (anhydride esters) for anti-inflammatory activity — Queeny Dasgupta et al., 2017

INTRODUCTION

Polymeric materials containing functional bioactives have found various applications in tissue engineering ( Agnihotri et al., 2004; Erdmann et al., 2000). Bioactive moieties such as drugs ( Dash and Konkimalla, 2012;Hoffman, 2012), growth factors ( Dang et al., 2016;Madry et al., 2013;Selcan Gungor-Ozkerim et al., 2014) and genes ( Shea et al., 1999) have been integrated into the polymer matrix simply by physical mixing or by a more intricate incorporation into the chemical structure ( Stebbins et al., 2015a). The chemical modifications include incorporation of the molecules onto pendant side chains ( Khorsand et al., 2013;RegnierDelplace et al., 2013) or the polymer backbone ( Dasgupta et al., 2016a;Dasgupta et al., 2016b).
Introduction of new functional groups and/or activation of the already present groups (Chandorkar et al., 2015) are used as strategies to incorporate drugs/ biomolecules ( Magana et al., 2016). The necessity of including such bioactive molecules into the current generation biomaterials has arisen from the need to combat issues like implantation induced inflammation ( Kzhyshkowska et al., 2015;Xia and Triffitt, 2006), microbial infection, and to minimize the body's own rejection response ( Anderson et al., 2008;Franz et al., 2011). There has, therefore, been a growing interest in the design and synthesis of completely biodegradable polymeric materials. These materials are capable of performing their function in the desired timescale, eventually get degraded and are safely cleared from the body ( Liu et al., 2012).
A major concern with these biodegradable materials has been the considerable toxicity of the degradation products ( Bhattacharyya et al., 2015;Taylor et al., 1994). This has generated substantial interest in formulating these polymers from monomers that are generally regarded as safe (GRAS) by the US FDA. Sugars and their alcohols are generally considered non-toxic because of their easy dissolution and metabolism inside the body. Sugar alcohols also feature in the GRAS list and currently find applications as sweeteners in chewing gums and the food industry ( Kroger et al., 2006). These multifunctional alcohols (polyols) have been

extensively used in the field of tissue engineering (Bruggeman et al., 2008). The secondary and tertiary (and other non-terminal) -OH groups have been predominantly utilized as sites for crosslinking to occur. These polymers are highly elastomeric thermosets and drugs have been incorporated in the polymer backbone ( Dasgupta et al., 2015;Dasgupta et al., 2016b). Although these systems exhibit controlled release, they suffer from drawbacks such as low drug loading and lack of processability due to insolubility. Another major shortcoming is that of the high temperature required for the crosslinking reaction. Many drugs are unstable at such high temperature, thereby, limiting the scope of such systems. Therefore, the challenge is to develop noncrosslinked, linear systems. Recently, a linear poly(anhydride ester) based on mannitol for ibuprofen release applications has been synthesized ( Stebbins et al., 2015b). This polymer is soluble, has high drug loading, anti-inflammatory properties and shows no cytotoxicity.
Exploiting the non-terminal -OH groups in the alcohol as sites for drug attachment ensures high drug loading, controlled release and good processability. Thus, developing new linear polymers with drugs in the backbone is of prime interest (Bien-Aime et al., 2016;Faig et al., 2016;Griffin et al., 2011). Several drug-polymer conjugates have been synthesized. Drugs conjugated to poly(ethylene glycol) have been utilized in making polymer-prodrug conjugates (Khandare and Minko, 2006). However, the polymer has to be suitably modified to enhance its low drug loading. Other drug delivery systems such as poly(ethyleneimine) ( Veiseh et al., 2010) (PEI) and poly(amidoamine ) ( Khandare et al., 2005) (PAMAM) have also been used to deliver drugs because of their high branching. However, these polymers have limited usage due to their high toxicity ( Albertazzi et al., 2012).
In this study, xylitol based polymers have been chosen because they have lower degradation rates compared to other polyol based polymers, resulting in better cell attachment (Bruggeman et al., 2008). Polyols such as mannitol have certain effects on cells

including increasing vasopermeability in endothelial cells ( Fortin et al., 2000) and decreasing blood viscosity when administered. Xylitol, being comparatively inert, is unlikely to interfere with the action of aspirin particularly in applications such as antithrombosis.
Aspirin (acetylsalicylic acid) is an analgesic, anti-pyretic and a non-steroidal antiinflammatory drug ( Schror and Voelker, 2016). It features in the WHO model list of essential medicines for the human system and is a commonly administered over the counter drug.
However, its broad range properties demand the design of a controlled release system. Aspirin exhibits antithrombotic effects by inhibition of prostaglandin G/H synthesis, but the rapid dosage of aspirin has an adverse effect on the prostacyclin (another inhibitor of platelet activation) due to this inhibition ( Clarke et al., 1991). Controlled release of aspirin allows lower thromboxane synthesis without affecting the prostacyclin concentration. Aspirin is widely used to treat inflammation including specific applications like cerebral ischemia ( Hosp et al., 1985;Yan et al., 2013) and preventing platelet aggregation ( Goetzl et al., 2016). Treatment of these conditions makes it necessary to design controlled release systems for aspirin administration.
The present work focuses on the synthesis of a linear poly(anhydride ester) with xylitol in the backbone and aspirin as the chemically incorporated drug. The objective of this study are 3fold: (i) to synthesize an aspirin loaded linear poly(anhydride ester) with aspirin at the 2deg and 3deg OH positions of xylitol, (ii) to understand and provide insights into the physicochemical properties such as degradation and release and (iii) to understand its pharmacological stability, cytocompatibility and inflammatory activity in RAW 264.7 macrophages. The current synthesis procedure involves five steps but this formulation has significant advantages of being a good site specific drug delivery vehicle. Specifically, this polymer has significantly high drug loading as compared to other systems where the drug is grafted on the polymer. In addition, the drug in the backbone ensures that pharmacologically active drug is released periodically at the diseased site.
Polyesters that are normally synthesized from polyfunctional alcohols are crosslinked. Thus they cannot be casted or used as injectables. This system can be used as

Preparation and preliminary quality evaluation of aspirin/L-glutamate compound pellets. — Mengchang Xu et al., 2021

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely available to treat fever, pain, and arthritis, which is one of the most frequently prescribed drugs in the world [ 1 ]. NSAIDs exert their effects by inhibiting the activity of cyclooxygenase (COX). Common COX has two subtypes: COX-1 and COX-2. COX-1 is necessary to maintain certain normal functions of human body and participates in the synthesis of the prostate (PGs) required for normal cell activities. COX-2 increases expression under tissue injury and inflammation, while participates in the synthesis of mediate inflammation, pain, PGs. NSAIDs exert antipyretic, analgesic, and anti-inflammatory effects by inhibition of COX-2 activity, while exert antithrombotic effect by inhibition of COX-1 activity. According to the inhibitory mechanisms for COX, NSAIDs are divided into COX-1 high-selection inhibitors (such as, aspirin, indomethacin), COX-1 low-selection inhibitors (ibuprofen, acetaminophen), COX non-selection inhibitors (naproxen, diclofenac), COX-2 selection inhibitors (celecoxib, rofecoxib), and so on [ 2 ]. However, NSAIDs can cause severe gastrointestinal adverse reactions using for a long-term. Epidemiological studies found that about 20–30% of patients appear gastric ulcers and 2% suffer severe complications such as gastric bleeding or perforation and even death. The incidence of high-risk groups can reach to 10% [ 3 ]. The incidence of dyspepsia is 1.5–2 times that of non-drugs using [ 4 ]. About 5–15% of patients with rheumatoid arthritis discontinue drugs due to gastrointestinal adverse reactions [ 5 ]. It can be seen that the gastric injury effect of NSAIDs has become a huge obstacle to the clinical use of such drugs, and it is of great clinical significance to find a safe and effective way to prevent gastric injury caused by NSAIDs.
At present, the common methods to prevent gastric injury caused by NSAIDs include the combination use of antiulcer drugs or mucosal protection drugs, or use of selection COX-2 inhibitors, dual pathway inhibitors of COX and 5-LOX [ 6 ]. The most common anti-ul

cer drug to protect gastric injury caused by NSAIDs is proton pump inhibitor (PPI). PPI can effectively inhibit incidence of gastric ulcers caused by NSAIDs, while long-term use of PPI can cause fractures (hip, wrist, and spinal) and gastrointestinal microbial homeostasis [ 7 – 9 ]. Gastric mucosal protective drugs such as misoprostol can effectively reduce the gastric ulcer caused by NSAIDs, but the effect on dyspepsia is poor which limits its application [ 10 ]. COX-2 selection inhibitors can significantly reduce gastrointestinal adverse reactions [ 11 ]. COX and 5-COX dual pathway inhibitors have anti-inflammatory and analgesic effects almost no gastrointestinal side effects, but benzoxprofen was withdrawn from global market due to severe hepatotoxicity [ 12 ]. Now, there is still no ideal approach to gastric injury resistance caused by NSAIDs.
In recent years, researchers have shown that L-glutamic has gastrointestinal protection and functional regulation through multiple pathways including increasing mucus and bicarbonate secreation [ 13 ], increasing mucin expression, enhancing intercellular adhesion, inhibiting microbial invasion [ 14 , 15 ], enhancing the gastrointestinal mucosal barrier effect, reducing intestinal oxidative stress-induced damage, and promoting the repair of gastric damage [ 16 , 17 ]. In addition, L-glutamic is relatively safe for individual even pregnant women, lactating women and children [ 18 ]. Thus, L-glutamic is considered as a potential drugs which is an effective and safe way to reduce gastric mucosal damage caused by NSAIDs. In this work, we proposed effective dose of L-glutamate using aspirin as a model drug with stomach injury model of rats for gastrointestinal protection. We constructed a biphasic release compound formulation of aspirin (enteric) and L-glutamate and studied the prescription and process of compound preparation. This study provides a novel idea for protection of gastric mucosa damage caused by NSAIDs.
Aspirin (>100%) was pharmaceutical grade and purchased from Shandong Xinhua Pharmaceutical Co., Ltd., China. L-glutamate (>98.5%) was pharmaceutical grade and purchased from Jizhou Huayang Chemical Co., Ltd., Salicylic acid (>99.9%) was pharmaceutical grade and purchased from China National Institute for Food and Drug Control. Sodium carboxymethyl cellulose, PVP K30, and hyp

romellose were AR grade and purchased from Anhui Sunward Pharmaceutical Excipients Co., Ltd., China. Hydrochloric acid, ethanol (95%), and tartaric acid were analytical grade and purchased from Sinopharm Chemical Reagent Co., Ltd., China. Glyceryl monostearate (GMS) was AR grade and purchased from Hunan Huihong Reagent Co., Ltd., China. Steria was pharmaceutical grade and purchased from Qufu Shengren Pharmaceutical Co., Ltd., China. All chemicals were used without further purification.
Twenty-four SD rats were randomly divided into six groups: blank control group, aspirin 25, 50, 100, 200, 400 mg/kg group, respectively. Aspirin was intragastric administrated for 7 days and once a day. The statistic data from designed experiments, see Table. 1 . The rate of gastric ulcer was 100% when the dose of aspirin was equal or greater than 200 mg/kg. Therefore, we use 200 mg/kg aspirin to build gastric injury model of rats. Table 1 Lesion index of gastric mucosal and rate of gastric ulcer of rats induced by aspirin (Mean ± SD, n = 4) Dose of aspirin (mg/kg) Lesion index Rate of gastric ulcer (%) 0 0 0 25 0 0 50 0.75 ± 1.50 25 100 4.50 ± 3.42 75 200 25.50 ± 2.65 100 400 29.50 ± 4.36 100
Lesion index of gastric mucosal and rate of gastric ulcer of rats induced by aspirin (Mean ± SD, n = 4)
Seventy-two SD rats were randomly divided into nine groups: blank control group, model group, L-glutamate group (25, 50, 100, 200, 400, 800 mg/kg), and positive control group (ranitidine hydrochloride, 30 mg/kg) (see Table S1). The drugs were intragastric administrated for 7 days and once a day (Tables 2 and 3 ). The gastric scale was tested to evaluate the injury protection performance of different doses (see Fig. 1 ) and statistic data of inhibition

Preparation and activity of glycosylated acetylsalicylic acid. — Gangliang Huang et al., 2018

1 Introduction Acetylsalicylic acid, also known as aspirin, is a antipyretic analgesic with a long history. We all know that this medicine can be used to treat colds, fever, headaches, toothache, joint pain, and rheumatism. It also can inhibit platelet aggregation, prevent and treat ischemic heart disease, cardiopulmonary infarction, cerebral thrombosis and other diseases ( De and Renda, 2012 ). In addition, it has shown that acetylsalicylic acid has anti-cancer effect ( Rothwell et al., 2012 ). The US working group for preventive services has issued a guide that acetylsalicylic acid can be used as the primary prevention of cardiovascular disease and colorectal cancer. The guideline proposed for the first time that high-risk groups of non-colorectal cancer could use acetylsalicylic acid for primary prevention of colorectal cancer ( Mora and Manson, 2016 ). It indicated that taking a certain dose of acetylsalicylic acid daily might effectively block the growth of breast cancer ( Mc Menamin et al., 2017 ). Moreover, acetylsalicylic acid may have a certain inhibitory effect on colon cancer ( Voora et al., 2016 ), gastrointestinal cancer ( Jankowska et al., 2010 ), prostate cancer ( Choe et al., 2012 ) and other cancers. Glycosylation modifications are widely found in natural products, such as clinical antibiotic erythromycin, antiparasitic insecticide avermectins, and anticancer drug doxorubicin, which are with glycosylation modification ( Huang and Mei, 2014 ). Glycosylation can improve the water solubility of drug, reduce toxicity and improve the activity. Moreover, it usually directly involves in the interaction of drug with the target. The activity of deglycosylated drug will be greatly affected. So, the glycosylation modification of drug plays an important role in biological activity ( Huang et al., 2016 ). In addition, because anticancer drugs lack selectivity, tumor chemotherapy has serious side-effects. An ideal solution to the problem is the antibody-directed enzyme prodrug therapy (ADEPT) and the prodrug monotherapy (PMT) ( Tietze and Schmuck, 2011 ). Using the principle of McAb orientation, the specific activating enzyme for prodrug is cross

linked and selectively bound to the tumor site. The prodrug can be specifically transformed into active molecule in tumor tissues, which effectively solves the problems of low concentration in tumor tissues and damage to normal tissues for drug. This prodrug design is called ADEPT. PMT method is to make anticancer drug into a prodrug containing enzyme substrate structure, and release the drug under the special enzyme action of cancer cells to play a therapeutic role. So far, there has been no report on the modification of acetylsalicylic acid by glycosylation. Therefore, we try to carry out research work in this area. d -galactose can be used as a vector for prodrug design ( Melisi et al., 2011 ). So, this galactosylated acetylsalicylic acid prodrug was prepared in four-step reaction. The inhibitory activity of acetylsalicylic acid and its galactosylated prodrug was tested. In addition, their anticancer activity to cancer cells was also assayed by ADEPT and PMT. 2 Experimental method 2.1 Preparation of peracetylated d -galactose 2 The acetic anhydride (70 mL) d -galactose (5 g) was slowly added to the reaction bottle. Then, 70 mL of anhydrous pyridine was added under stirring. This reaction was lasted for 20 h at 25 °C. After the reaction was complete, the reaction mixture was poured into ice water, which was fully stirred until room temperature. After filtration, The crude product was recrystallized with water/methanol (v/v = 1/2). Peracetylated
d -galactose 2 Yield: 92%; 1 H NMR (300 MHz, CDCl 3 ): δ 6.34 (d, 1H α , J 1 , 2 1.5 Hz, H-1α), 5.63 (d, 1H β , J 1 , 2 1.5 Hz, H-1β), 5.50 (dd, 1H, J 3 , 4  < 1.0 Hz, J 4 , 5 1.3 Hz, H-4), 5.

34–5.29 (m, 2H, H-2, H-3), 4.31 (dt, 1H, J 5 , 6 6.5 Hz, H-5), 4.16–4.01 (m, 2H, H-6a, H-6b), 2.14, 2.10, 2.00, 1.98, 1.97, 1.96 (all s, 15H, 10  ×  C(O)CH 3 ); 13 C NMR (75 MHz, CDCl 3 ): δ 170.8, 170.5, 170.3, 169.3, 167.5 (5  ×  C
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O), 102.0 (C-1β), 101.5 (C-1α), 68.8 (C-5), 68.0 (C-3 and C-4), 66.6 (C-2), 61.5 (C-6), 21.3, 21.1, 20.9, 20.8, 20.6 (5  ×  C(O)CH 3 ); ESI-MS: m / z  = 413.3397 [M + Na] + . 2.2 Preparation of αd -galactopyranosyl bromide 4 The peracetylated galactose 2 (5 g, 12.8 mmol) was added into the reaction bottle. Then 50 mL of hydrogen bromide-acetic acid (33%) was added dropwise at 0 °C. After reaction for 2 h at 25 °C, 150 mL of CH 2 Cl 2 was added. The mixture was washed with ice water, and the organic layer was dried with a desiccant (MgSO 4 ). After vacuum distillation, peracetylated α-galactosyl bromide 3 was provided in the yield of 97%. Compound 3 was hydrolyzed with 20 mL of dilute HBr solution (1 mol/L) for 2 h

Tandem Transesterification-Esterification Reactions Using a Hydrophilic Sulfonated Silica Catalyst for the Synthesis of Wintergreen Oil from Acetylsalicylic Acid Promoted by Microwave Irradiation. — Sandro L Barbosa et al., 2022

Wintergreen ( Gaultheria procumbens L.), also known as checkerberry or teaberry, is a small, ericaceous plant found growing in the undergrowth of dense forests in the U.S. Wintergreen is cultivated for use in the landscape industry, and it is the source of the essential oil of wintergreen (WO) [ 1 , 2 ]. The essential oil of wintergreen is prepared commercially by steam distillation; however, the most commonly used form of WO is synthetic. Wintergreen is now commonly used as a flavoring agent, but its leaves were historically used by North American natives for the treatment of aches and pains due to their “aspirin-like” quality. In fact, WO, the most common salicylate in commercial wintergreen preparations, and is routinely used in topical ointments for the treatment of inflammation [ 2 ].
WO is a clear liquid with a peppermint and minty scent, which most likely serves as a defense against herbivores. For example, when a plant is infected with herbivorous insects, the production of WO attracts other insects that kill these herbivorous insects [ 3 ]. WO can also be used by plants as a pheromone to warn other plants of pathogens, such as the tobacco mosaic virus [ 4 ], and it is used as a clearing agent for preparing slides of Aedes mosquito larvae for microscopic examination [ 5 ]. It is also extensively used in the synthesis of solvents, perfumes, cosmetics, food preservatives, chiral auxiliaries, plasticizers, drugs, and pharmaceuticals [ 6 , 7 ]. Ribnicky et al., (2003) determined the presence of salicylates, other than methyl salicylate, that could act as alternatives for aspirin [ 8 ]. Recently, the authenticity of methyl salicylate (MS) in the essential oils from Gaultheria procumbens L. and Betula lenta L. was determined using isotope ratio mass spectrometry [ 9 ].
Among the methods found in the literature for the synthesis from salicylic acid (SA), the preparation of methyl salicylate (MS) using diazotization chemistry is emphasized [ 10 ]. In this previous experiment, the use of diazonium salts for the replacement of an aromatic amine group by a phenolic hydroxyl was demonstrated. Many reports have been published on the synthesis

of WO by esterification of SA with dimethyl carbonate (DMC), such as, “Green synthesis of WO using novel sulfated iron oxide-zirconia catalyst” [ 11 ]. Sreekumar et al., reported the reaction of SA with DMC using zeolite, wherein monomethylation was observed [ 12 ]. Kirumakki et al., obtained a 90% conversion of salicylic acid and 95% selectivity in the reaction of SA with DMC over zeolites when treated for 4 h at 135 °C [ 13 ]. Zheng et al., reported 98% conversion and 96% selectivity with DMC over the AlSBA15-SO 3 H catalyst when treated for 8 h at 200 °C [ 14 ]. Su et al., obtained 99% conversion of SA and 77% selectivity for the reaction of SA with DMC over mesoporous aluminosilicate [ 15 ], and Zhang et al., reported 93% conversion and 99% selectivity with methanol using Ce 4+ -modified cation exchange resins when treated for 12 h at 95 °C [ 16 ]. In all of these studies, equilibrium in the esterification reaction was overcome using dimethyl carbonate, instead of methanol, as the methylation agent.
Some studies have reported the formation of MS from the esterification reaction of SA with MeOH as a methylation agent, using different solid catalysts. Hua Shi et al., reported that a variety of Brønsted acidic ionic liquids were screened as catalysts for the esterification of salicylic acid in a microwave-accelerated process [ 17 ].
Esterification or transesterification using microwave irradiation, in addition to being environmentally friendly, is also marked by a considerable reduction in reaction time in comparison with conventional esterification [ 18 , 19 ]. Furthermore, to the best of our knowledge, tandem esterification-transesterification of acetylsalicylic acid (ASA) in hydrophilic sulfonated silica catalyst has not yet been achieved. There are few studies that have reported the transesterification/esterification of ASA. No report of the use of liquid or solid catalysts using the principles of Green Chemistry has been published.
As a part of an ongoing research on the use of the SiO 2 –SO 3 H catalyst for clean synthesis [ 20 ] using the principles of

Green Chemistry, this catalyst was used in the highly selective, one-pot, tandem, transesterification–esterification reactions of ASA with MeOH in the microwave-accelerated synthesis of MS. A high catalytic activity in a very short period of time in an inexpensive process to produce high yields of highly pure MS from ASA was observed. The synthesis of MS directly by methylation of salicylic acid was also achieved. The stability and re-use of SiO 2 –SO 3 H was also examined.
All the reagents (analytical grade), including ASA, were supplied by Vetec, São Paulo, Brazil, and were used without further purification.
All the reactions were monitored by GC–MS. The compositions of the reaction products were determined on a GC–MS-QP 2010/AOC 5000 AUTO INJECTOR/Shimadzu Gas Chromatograph–Mass Spectrometer equipped with a 30 m Agilent J&W GC DB-5 MS column (Santa Clara, CA, USA). Direct insertion spectra were measured at 70 eV. Quantitative analyses were performed on a Shimadzu GC-2010 gas chromatograph (Kyoto, Japan) equipped with a flame ionization detector under the same conditions as specified for the GC–MS analyses [ 20 ]. We also used a GC–FID, equipped with a 30 m Agilent J&W GC DB-17 MS column. Final hold time was approximately 20 min, where the temperature ramp started at 70 °C for 5 min, reaching 270 °C, remaining at this temperature for 5 min using nitrogen as the carrier gas (See Supplementary Materials ). 1 H- and 13 C-NMR spectra were recorded on Bruker Avance 400 Spectrometers (Billerica, MA, USA) using deuterated methanol as the solvent and TMS as the internal reference [ 20 ]. The purification of the products was achieved by flash column chromatography using a mixture of hexane/ethyl acetate in a 9/1 proportion as the eluent. The MW reactions were performed in 10 mL G-10 vials of an Anton Paar single-mode MW Monowave 300 synthesis reactor (Graz, Austria), powered by an 850 W magnetron, and equipped with temperature sensor and magnetic stirring [ 21 ].
The preparation of silica gel and the sulfonated silica, SiO 2 –SO

Optimizing Acetic Anhydride Amount for Improved Properties of Acetylated Cellulose Nanofibers from Sisal Fibers Using a High-Speed Blender. — Romi Sukmawan et al., 2023

Recently, cellulose nanofibers
(CNFs) have received significant
attention due to their excellent properties such as high strength
and stiffness, high aspect ratio, very light, renewable ability, biodegradability,
biocompatibility, high crystallinity, high surface activity, low toxicity,
good rheological, and optical properties. 1 − 5 Because of their attractive advantages, CNFs have
attracted increasing interest in many applications, including papermaking,
coating additives, security paper, food packaging, gas barrier, and
reinforcing agents in polymer nanocomposites. 6 CNFs are fabricated by the mechanical methods of cellulose-based
materials, which are usually obtained after the removal of amorphous
components such as hemicellulose, lignin, wax, and oils through chemical
treatments. 7 The mechanical methods include
high-pressure homogenization, micro fluidization, ultra-sonication, 8 high-speed disintegration, 9 and grinding. 10
Although
CNFs have excellent potential as a reinforcing agent in
nanocomposites, as described above, it is difficult for CNF particles
to be dispersed homogeneously in a non-polar polymer matrix, which
makes the strengthening effect insignificant. 11 The hydrophilic behavior is ascribed to the hydroxyl groups on the
surface of the cellulose fiber. 12 Therefore,
to reduce the surface hydrophilicity of CNFs and improve their properties,
it is necessary to carry out various surface modifications such as
esterification, etherification, silylation, and organic acid grafting. 13 , 14 Among those modifications, acetylation is a commonly used surface
modification in which the hydroxyl groups of cellulose are substituted
by less hydrophilic acetyl groups. 15 Acetylation
effectively reduces the number of hydroxyl groups in cellulose, thereby
increasing the hydrophobicity and reducing hydrogen bonds. 16
Numerous studies have been reported on
the acetylation of CNFs
isolated from different cellulose sources. The ACNF from the kenaf
fibers was successfully prepared by Jonoobi et al. 17 and Ashori et al. 18 The ACNF
from sisal fibers (SF) was also demonstrated by Trifol et al., 19

where the SF were treated using alkali, bleached,
and followed by acetylation. Zimmermann et al. 20 produced ACNF from microcrystalline cellulose (MCC) by
acetylation treatment at 120 °C for 3 h and then followed by
ultrafine grinding for 4 h. ACNF from cotton linter was reported by
Yuan et al. 21 where acetylated cellulose
nanofiber (ACNF) was prepared using a combination of acetylation and
high-pressure homogenization for stabilizing Pickering emulsion. The
properties of obtained ACNF are greatly affected by several factors,
such as the type of cellulose sources, the molar ratios of acetic
acid and acetic anhydride, the ratio of MCC to acetic anhydride, degree
of substitution (DS), blending time, and the type and amount of ester
groups. 16 , 22 − 24 Diop et al. investigated
the effect of the acetic acid/acetic anhydride ratio on the properties
of corn starch acetates. 22 They found that
the ratio of acetic acid/acetic anhydride strongly influenced the
crystallinity, surface morphology, water solubility, and water absorption
index of corn starch, and the best ratio of acetic acid/acetic anhydride
was achieved in 1:1. Zhou et al. demonstrated that the DS was increased
with increasing the molar ratio of acetic anhydride/acetic acid. 16 Cheng et al. produced ACNF prepared from corn
stalk MCC with different ratios of MCC to acetic anhydride using chemical-high-pressure
homogenization processes. 23 They found
that the DS was increased as the ratio of MCC to acetic anhydride
increased. Moreover, the crystallinity index (C r I) and
thermal stability were decreased with increasing the ratio of MCC
to acetic anhydride. Xu et al. successfully prepared acetylated cellulose
nanocrystals via a one-step reaction with varying amounts of acetic
anhydride from commercial MCC powder. 25 They demonstrated that both C r I and DS were found to
increase with increasing the acetic anhydride amounts.
In this
work, SF were used as a source of cellulose to make

CNFs
because SF have a high cellulose content (60–70%) 26 − 28 and were widely available in the province of Nusa Tenggara Barat,
Indonesia. Sisal fiber is extracted from the leaves of the Agave sisalana plant which is native to Mexico but
can now grow rapidly in tropical countries around the world, including
Indonesia. Therefore, it is very interesting to produce CNFs extracted
from SF. To the best of the author’s knowledge, no studies
on the preparation of acetylated cellulose nanofibers (ACNFs) from
SF using a high-speed blender with varying amounts of acetic anhydride
have been reported. A high-speed blender was used in this work because
it was proven to be effective in making CNFs with low energy consumption. 9 , 29 , 30
In the present work, the
ACNFs with different degrees of substitution
were produced from the SF. The SF were first bleached using the alkaline
hydrogen peroxide (AHP) solution. Then, the AHP-treated SF were modified
using an acetylation process with different amounts of acetic anhydride,
and the nanofibrillation was performed using a high-speed blender.
The effect of the amounts of acetic anhydride on the characteristics
of ACNFs was investigated in the present study. The characteristics
of ACNF were evaluated using attenuated total reflectance-Fourier
transform infrared (ATR-FTIR), X-ray diffraction (XRD), scanning electron
microscope (SEM), thermogravimetric analysis (TGA), and the measurements
of the DS and water contact angle.
SF were obtained from Sumbawa
Bangkit Sejahtera Inc., Nusa Tenggara Barat, Indonesia. The fibers
were cultivated in West Nusa Tenggara Province, Indonesia, for a cultivation
period of 2–3 years. The sulfuric acid (95–97%), glacial
acetic acid (100%), acetic anhydride (>97%), sodium hydroxide (NaOH),
and hydrogen peroxide (30% in water) were bought from Sigma-Aldrich,
USA. In addition, methanol (≥99%) and acetone (95%) were used
as solv

Solubility prediction: aspirin in Water

Solute LogP: 1.19
Solvent LogP: -1.38 (very polar protic)
|Delta LogP|: 2.57
Prediction: Likely insoluble

Note: This is a polarity-based estimate. Hydrogen bonding, ionization, and specific molecular interactions may alter actual solubility.

Solubility prediction: acetylsalicylic acid in Water

Solute LogP: 1.19
Solvent LogP: -1.38 (very polar protic)
|Delta LogP|: 2.57
Prediction: Likely insoluble

Note: This is a polarity-based estimate. Hydrogen bonding, ionization, and specific molecular interactions may alter actual solubility.

Research will be limited to:
- Solute: Acetylsalicylic Acid
- Solvent: Water
- Temperature Range: 0-5°C
- Property: Solubility

Strategy: The objective is to find specific solubility data for acetylsalicylic acid (aspirin) in water within the narrow temperature range of 0-5°C. Solubility data for aspirin is commonly cited at room temperature (approx. 3 mg/mL at 25°C), but values near the freezing point are less common in general references. I will search for experimental data tables, chemical handbooks (like CRC or Lange's), or peer-reviewed studies that provide precise measurements or a solubility curve equation that can be used to interpolate the value at 0-5°C.
Queries:
- solubility of acetylsalicylic acid in water at 0 C 5 C g/100mL
- "acetylsalicylic acid" water solubility temperature dependence data table
- "aspirin" solubility in water 273K 278K

🔍 Reading and summarizing 2 new websites...

1. Salicylic acid - Wikipedia
2. Acetylsalicylic acid - Sciencemadness Wiki

Found 2 websites. Summarized content:

Salicylic acid - Wikipedia
Acetylsalicylic acid is not directly discussed on this page, only salicylic acid. The solubility of salicylic acid in water at 0°C is 1.24 g/L. The page does not provide the solubility between 0-5°C.

Acetylsalicylic acid - Sciencemadness Wiki
Acetylsalicylic acid solubility in water is 0.3 g/100 ml at 20 °C. The provided text does not contain information on the solubility of acetylsalicylic acid in water specifically at 0-5°C.

Solubility prediction: aspirin in Ethanol

Solute LogP: 1.19
Solvent LogP: -0.31 (polar protic)
|Delta LogP|: 1.50
Prediction: Partially soluble

Note: This is a polarity-based estimate. Hydrogen bonding, ionization, and specific molecular interactions may alter actual solubility.

Research will be limited to:
- Substance: Aspirin
- Solvent: Ethanol
- Temperature: 78°C and 0°C
- Units: grams per 100mL

Strategy: The objective is to find the specific solubility values for aspirin (acetylsalicylic acid) in ethanol at two temperature extremes: 0°C and 78°C (the approximate boiling point of ethanol).

Current state: No data has been retrieved yet.
Missing info: Specific numerical values in g/100mL for these two temperatures.

Strategy: I will search for solubility curves or tables for aspirin in ethanol. If values are found in different units (e.g., mole fraction or g/L), I will convert them to g/100mL. 78°C is the boiling point, so I will look for 'solubility at boiling point' if 78°C isn't explicitly indexed.
Queries:
- solubility of aspirin in ethanol at 0°C and 78°C g/100mL
- "aspirin" ethanol solubility temperature curve data
- acetylsalicylic acid solubility in ethanol at boiling point and 0 C

🔍 Reading and summarizing 4 new websites...

1. IUPAC-NIST Solubility Data Series. 102. Solubility of Nonsteroidal ...
2. Salicylic Acid – Sodium Phenylbutyrate | Trissel's Stability of ...
3. [PDF] Modeling Solubility of Acetylsalicylic Acid in Aspen Plus
4. [PDF] Measurement solubility of Acetylsalicylic Acid in water and alcohols

Found 2 websites. Summarized content:

IUPAC-NIST Solubility Data Series. 102. Solubility of Nonsteroidal ...
Not relevant. (The provided content is a security verification page, not solubility data.)

[PDF] Modeling Solubility of Acetylsalicylic Acid in Aspen Plus
The article "Modeling Solubility of Acetylsalicylic Acid in Aspen Plus" studies the solubility of aspirin in ethanol, acetone, propylene glycol, and 2-propanol within the temperature range of 270-360 K using Aspen Plus V14.

While the article does not explicitly state the exact solubility of aspirin in ethanol at 78°C (351K) and 0°C (273K), it provides data and figures that can be used to estimate these values.

Based on Table 1 from the article:

• At 351 K (approximately 78°C): The simulated solubility, Xexp of acetylsalicylic acid in ethanol using the NRTL model is approximately 0.38906.

• At 274.5 K (approximately 0°C): The The simulated solubility, Xexp of acetylsalicylic acid in ethanol using the NRTL model is approximately 0.02937.

Please note that these values are in mole fraction. The article does not provide the density of the solutions. Therefore, it is impossible to convert to grams per 100mL from the given information.

Mathematical Error: 'list' object has no attribute 'get'

🧪 Protocol Master: synthesis of aspirin (acetylsalicylic acid) from salicylic acid and acetic anhydride using an acid catalyst

Method: Simulation validated (21 cycles) | Date: 2026-03-11

I. Materials & Equipment

• [ ] Salicylic acid ($\ce{C7H6O3}$)
• [ ] Acetic anhydride ($\ce{C4H6O3}$)
• [ ] 85% Phosphoric acid ($\ce{H3PO4}$)
• [ ] Deionized water
• [ ] Ice
• [ ] 125 mL Erlenmeyer flask
• [ ] 400 mL Beaker (for water bath)
• [ ] 600 mL Beaker (for ice bath)
• [ ] 10 mL Graduated cylinder
• [ ] Glass dropper
• [ ] Glass stirring rod
• [ ] Thermometer
• [ ] Hot plate
• [ ] Buchner funnel and 250 mL filter flask
• [ ] Filter paper
• [ ] Vacuum pump
• [ ] Analytical balance
• [ ] Spatula
• [ ] Weighing boat

II. Step-by-Step Procedure

Step 1: Weigh out 2.00 g of salicylic acid ($\ce{C7H6O3}$) into a 125 mL Erlenmeyer flask.
- Note: Perform all steps involving acetic anhydride inside a functional fume hood.

Step 2: Add 5.0 mL of acetic anhydride ($\ce{C4H6O3}$) to the flask and swirl gently to create a slurry.
- Note: Acetic anhydride is a lachrymator and corrosive; handle with care.

Step 3: Add 5 drops of 85% phosphoric acid ($\ce{H3PO4}$) catalyst directly into the mixture using a glass dropper.
- Note: Phosphoric acid is highly corrosive; avoid contact with skin and eyes.

Step 4: Prepare a water bath in a 400 mL beaker and heat it on a hot plate. Submerge the Erlenmeyer flask in the bath and maintain the internal reaction temperature between 50-60°C for 15 minutes.
- Note: Monitor the temperature closely with a thermometer. Do not exceed 60°C to prevent product decomposition.
- Note: The reaction is complete when the solid crystals have fully dissolved and the solution is clear.

Step 5: Remove the flask from the heat and add 20 mL of chilled deionized water dropwise at first, then more rapidly once the initial exothermic reaction with excess anhydride subsides.
- Note: The addition of water decomposes excess acetic anhydride into acetic acid, which will evolve pungent vapors.

Step 6: Place the flask into an ice-water bath (0-2°C). Use a glass rod to scratch the inner walls of the flask to induce nucleation and crystallization.
- Note: Maintain the flask in the ice bath until a heavy precipitation of white aspirin crystals is observed.

Step 7: Assemble a vacuum filtration apparatus with a Buchner funnel and filter paper. Dampen the paper with ice-cold water to create a seal, then filter the aspirin slush under vacuum.
- Note: Ensure the mother liquor is pulled through completely.

Step 8: Wash the crude crystals twice with 5 mL portions of ice-cold deionized water and continue the vacuum for 5 minutes to air-dry the product.
- Note: Washing removes residual phosphoric acid and acetic acid. Using room-temperature water will significantly decrease yield.

III. Troubleshooting & Common Failures

Derived directly from failed simulation attempts:

• ⚠️ Do not add water rapidly to the hot reaction mixture, as the exothermic decomposition of acetic anhydride can cause splashing and rapid evolution of acidic vapors.
• ⚠️ Avoid exceeding 60°C during the heating phase, as high temperatures may lead to the hydrolysis of aspirin back into salicylic acid.
• ⚠️ Do not use incorrect SMILES strings (e.g., 'C(=O)(C1=CC=CC=CC1=C(O)=O)O') when performing computational molecular weight checks, as this will lead to calculation errors.
• ⚠️ Ensure the volume of ethanol used for recrystallization (if performed) is carefully calculated; using an excessive amount will prevent the aspirin from precipitating during cooling.