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Cold synthesis of propionylsalicylic acid

ID: 160366  |  No.: 627  |  Institut für Chemieinformation

Student experiment from Year 10 onwards

Category: organic synthesis, Working techniques

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Permanent archiving (DOI)

No permanent DOI has been generated for this experiment yet.

Procedure

The round-bottomed flask is clamped to the stand in the fume cupboard in such a way that the lifting platform, magnetic stirrer and water bath can be placed underneath it and removed again without obstruction.

Using the powder funnel, add 5 g of salicylic acid/DMAP-Germisch and the magnetic stirring rod to the round-bottomed flask. Wear disposable nitrile gloves as splash protection.

The thermometer is placed in the side neck (secured with a ground-glass clamp).

3.9 g of propionic anhydride is now added via the powder funnel.

Remove the powder funnel (collect any dripping residue in a beaker), fit the reflux condenser and clamp it to the stand (do not overtighten the apparatus).

A moderate flow of cooling water is set.

The magnetic stirrer with the water bath is positioned beneath the flask using the lifting platform, so that there are still a few millimetres’ clearance to the bottom of the flask, but the mixture can be stirred thoroughly.

Whilst stirring, the mixture is now stirred for 15 minutes, initially at room temperature. The reaction mixture heats up to approx. 40°C as the reaction begins. 

The thermometer is removed and the side neck is sealed with a ground-glass stopper (or screw cap).

The flask is removed from the condenser, sealed with another ground-glass stopper (or screw cap) and placed in an ice bath.

The white precipitate formed in the ice bath is scraped off and rinsed three times with 10 ml of ice-cold pure water on each occasion (using the spray bottle, which has been cooled in the ice bath beforehand).

The precipitate of propionylsalicylic acid, which has been largely dried on the Nutsch filter, is left to dry completely in the air (or in a drying oven at 50 °C; however, all remaining traces of propionic acid or propionic anhydride must then have been washed out).

Alternatively to the final step, the crude product can be placed in an Erlenmeyer flask for purification with 16 ml of pure water and 4 ml of ethanol.

The flask is suspended on a stand in a water bath and heated to a maximum of 80 °C, whilst being swirled repeatedly until the solid has dissolved.

The flask is then left to cool undisturbed in the ice bath. A weighting ring fitted to the flask prevents it from tipping over.

Equipment & materials

100-ml double-necked round-bottom flask (2 x NS 29 or NS 29 and a side neck NS 14.5, or with threaded fittings)

Reflux condenser NS 29 or with threaded connection

Powder funnel NS 29

Disposable pipette

25-ml measuring cylinder

Balance (accurate to at least 1 g)

100 ml Erlenmeyer flask (wide-neck)

Filter funnel with suitable filter paper 

Tubing connector

Magnetic stirring rod

Magnetic stirrer with water bath

Lifting platform

Glass or digital thermometer, fitting the ground joint on the side neck of the round-bottomed flask (thermometer with a ground joint or a suitable threaded tube with a septum)

Teflon sealing rings or sleeves, otherwise ground joint grease (preferably water-soluble)

Bowl containing a mixture of ice and water (glass, plastic or metal; the round-bottomed flask must fit comfortably inside)

Cork ring for the round-bottomed flask (for storage)

Weighted ring for the Erlenmeyer flask (can also be fashioned from a length of electrical cable)

Further information on equipment is available in the equipment management system.

Hazardous substances
Name Formula CAS no. H-statements P-statements Pictograms
Salicylsäure OHC₆H₄COOH 69-72-7
H302 – Harmful if swallowed.
German original: Gesundheitsschädlich bei Verschlucken.
H318 – Causes serious eye damage.
German original: Verursacht schwere Augenschäden.
H361d – Is likely to harm the unborn child.
German original: Kann vermutlich das Kind im Mutterleib schädigen.
P202 – Read and understand all safety instructions before use.
German original: Vor Gebrauch alle Sicherheitshinweise lesen und verstehen.
P264 – After use … wash thoroughly.
German original: Nach Gebrauch ... gründlich waschen.
P280 – Wear protective gloves / protective clothing / eye protection / face protection.
German original: Schutzhandschuhe / Schutzkleidung / Augenschutz / Gesichtsschutz tragen.
P301+P312 – IF SWALLOWED: If you feel unwell, call the POISON INFORMATION CENTRE / a doctor ...
German original: BEI VERSCHLUCKEN: Bei Unwohlsein GIFTINFORMATIONSZENTRUM / Arzt ... anrufen.
P308+P313 – IN CASE OF EXPOSURE OR IF AFFECTED: Seek medical advice / seek medical assistance.
German original: BEI Exposition oder falls betroffen: Ärztlichen Rat einholen / ärztliche Hilfe hinzuziehen.
P305+P351+P338 – IF IN EYES: Rinse gently with water for several minutes. Remove any contact lenses if possible. Continue rinsing.
German original: BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Vorhandene Kontaktlinsennach Möglichkeit entfernen. Weiter spülen.
GHS05, GHS07, GHS08
Propionsäure C₂H₅COOH 79-09-4
H226 – The liquid and vapour are flammable.
German original: Flüssigkeit und Dampf entzündbar.
H314 – Causes severe skin burns and serious eye damage.
German original: Verursacht schwere Verätzungen der Haut und schwere Augenschäden.
H335 – May irritate the respiratory tract.
German original: Kann die Atemwege reizen.
P210 – Keep away from heat, hot surfaces, sparks, open flames and other sources of ignition. Do not smoke.
German original: Von Hitze, heißen Oberflächen, Funken, offenen Flammen und anderen Zündquellen fernhalten. Nicht rauchen.
P233 – Keep the container tightly closed.
German original: Behälter dicht verschlossen halten.
P240 – Earth the container and the equipment to be filled.
German original: Behälter und zu befüllende Anlage erden.
P280 – Wear protective gloves / protective clothing / eye protection / face protection.
German original: Schutzhandschuhe / Schutzkleidung / Augenschutz / Gesichtsschutz tragen.
P303+P361+P353 – IF IN CONTACT WITH THE SKIN (or hair): Remove all contaminated clothing immediately. Wash the skin with water or take a shower.
German original: BEI BERÜHRUNG MIT DER HAUT (oder dem Haar):Alle kontaminierten Kleidungsstücke sofort ausziehen. Haut mit Wasser abwaschen/duschen.
P305+P351+P338 – IF THE PRODUCT COMES INTO CONTACT WITH THE EYES: Rinse gently with water for several minutes. Remove any contact lenses if possible. Continue rinsing.
German original: BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Vorhandene Kontaktlinsennach Möglichkeit entfernen. Weiter spülen.
GHS02, GHS05, GHS07
Propionsäureanhydrid C₆H₁₀O₃ 123-62-6
H314 – Causes severe chemical burns to the skin and serious damage to the eyes.
German original: Verursacht schwere Verätzungen der Haut und schwere Augenschäden.
P280 – Wear protective gloves / protective clothing / eye protection / face protection.
German original: Schutzhandschuhe / Schutzkleidung / Augenschutz / Gesichtsschutz tragen.
P363 – Wash contaminated clothing before wearing it again.
German original: Kontaminierte Kleidung vor erneutem Tragen waschen.
P301+P330+P331 – IF SWALLOWED: Rinse out the mouth. DO NOT induce vomiting.
German original: BEI VERSCHLUCKEN: Mund ausspülen. KEIN Erbrechen herbeiführen.
P303+P361+P353 – IF IN CONTACT WITH THE SKIN (or hair): Remove all contaminated clothing immediately. Wash the skin with water or take a shower.
German original: BEI BERÜHRUNG MIT DER HAUT (oder dem Haar):Alle kontaminierten Kleidungsstücke sofort ausziehen. Haut mit Wasser abwaschen/duschen.
P304+P340+P310 – IF INHALED: Move the person to fresh air and ensure they can breathe freely. Call a POISON INFORMATION CENTRE or a doctor immediately.
German original: BEI EINATMEN: Die Person an die frische Luft bringen und für ungehinderte Atmung sorgen. Sofort GIFTINFORMATIONSZENTRUM oder Arzt anrufen.
P305+P351+P338 – IF IT COMES INTO CONTACT WITH THE EYES: Rinse gently with water for a few minutes. Remove any contact lenses if possible. Continue rinsing.
German original: BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Vorhandene Kontaktlinsennach Möglichkeit entfernen. Weiter spülen.
GHS05
Propionylsalicysäure C₁₀H₁₀O₄ 6328-44-5
H302 – Harmful if swallowed.
German original: Gesundheitsschädlich bei Verschlucken.
H315 – Causes skin irritation.
German original: Verursacht Hautreizungen.
H319 – Causes severe eye irritation.
German original: Verursacht schwere Augenreizung.
H335 – May irritate the respiratory tract.
German original: Kann die Atemwege reizen.
P261 – Avoid inhaling dust, fumes, gas, mist, vapour or aerosols.
German original: Einatmen von Staub/Rauch/Gas/Nebel/Dampf/Aerosol vermeiden.
P305+P351+P338 – IF IN EYES: Rinse gently with water for several minutes. Remove any contact lenses if possible. Continue rinsing.
German original: BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Vorhandene Kontaktlinsennach Möglichkeit entfernen. Weiter spülen.
GHS07
Salicylsäure/Dimethylaminopyridin (9/1)
H302 – Harmful if swallowed.
German original: Gesundheitsschädlich bei Verschlucken.
H311 – Toxic if it comes into contact with the skin.
German original: Giftig bei Hautkontakt.
H315 – Causes skin irritation.
German original: Verursacht Hautreizungen.
H318 – Causes serious eye damage.
German original: Verursacht schwere Augenschäden.
H332 – Harmful if inhaled.
German original: Gesundheitsschädlich bei Einatmen.
H361 – Is likely to impair fertility or harm the unborn child <specify the specific effect, if known><specify the route of exposure, provided there is conclusive evidence that the risk does not exist via any other route of exposure>.
German original: Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen <konkrete Wirkung angebensofern bekannt><Expositionsweg angeben, sofern schlüssig belegt ist, dass die Gefahrbei keinem anderenExpositionsweg besteht>.
H370 – Causes damage to the organs <or list all affected organs, where known><specify the route of exposure, provided there is conclusive evidence that this risk does not exist via any other route of exposure>.
German original: Schädigt die Organe <oder alle betroffenen Organe nennen, sofern bekannt><Expositionsweg angeben, sofern schlüssig belegt ist, dass diese Gefahr bei keinem anderen Expositionsweg besteht>.
H412 – Harmful to aquatic organisms, with long-term effects.
German original: Schädlich für Wasserorganismen, mit langfristiger Wirkung.
GHS05, GHS06, GHS08

H/P statements: machine translation, with the German original below (authoritative). Name, formula, CAS no. and pictograms are not translated.

Personal protective equipment
  • Safety goggles must be worn.
    German original
    Eine Gestellschutzbrille ist zu tragen.
  • Disposable nitrile gloves are used as splash protection.
    German original
    Als Spritzschutz dienen Nitril-Einmalhandschuhe.
Protective measures
When fume cupboards are in operation, additional ventilation measures are required to supply fresh air; without this, a standard laboratory fume cupboard cannot function. These do not necessarily have to be technical ventilation measures.
German original
Beim Betrieb von Abzügen sind zusätzliche Lüftungsmaßnahmen für die Zufuhr von Zuluft, ohne die ein normaler Laborabzug nicht funktioniert, erforderlich. Dies müssen nicht zwingend technische Lüftungsmaßnahmen sein.
⚠ Hazards
  • by inhalation
    German original
    durch Einatmen
  • through skin contact
    German original
    durch Hautkontakt
  • through eye contact
    German original
    durch Augenkontakt
⚠ Further hazards and notes
  • Major leaks
    In the event of an accident, leave the room immediately and alert the fire brigade (telephone 112) and the school management; small leaks can be mopped up using chemical absorbent, but suitable personal protective equipment must be worn; pupils must keep a safe distance.
    German original
    Im Havariefall Raum unverzüglich verlassen und Feuerwehr (Telefon 112) sowie Schulleitung alarmieren, kleine Leckagen können mit Chemikalienbinder aufgenommen werden, hierbei ist geeigneter Selbstschutz erforderlich, Schülerinnen und Schüler halten sicheren Abstand.
Risk of breakage if the apparatus is tilted or if the flasks slip out of the ice bath. The crystal cake can become relatively hard; there is a risk of breakage and injury if it is prised out forcefully with a spatula. Propionic anhydride reacts violently on contact with water, particularly at higher temperatures. If the product is not washed thoroughly, vapours of propionic anhydride (or propionic acid) may be released as residues dry. Propionic anhydride has a noticeable vapour pressure even at room temperature and poses a significant hazard in the event of inhalation.
German original
Bruchgefahr beim Verkanten der Apparatur oder durch Herausrutschen der Kolben aus dem Eisbad. Der Kristallkuchen kann relativ hart werden, Bruch- und Verletzungsgefahr, wenn dieser mit Gewalt mit einem Spatel herausgestemmt wird. Propionsäureanhydrid reagiert heftig beim Kontakt mit Wasser, besonders bei höheren Temperaturen. Wenn das Produkt nicht ausreichend gewaschen wird, können beim Trocknen von Anhaftungen Propionsäureanhydrid- (oder Propionsäure-)dämpfe frei werden. Propionsäureanhydrid hat auch bei Raumtemperatur einen merklichen Dampfdruck und stellt bei inhalativer Exposition eine erhebliche Gefährdung dar.
⚠ Safety instructions

The experiment places relatively high demands on experimental skills; these must therefore be taught beforehand.

The release of propionic anhydride must be minimised. For this reason, in addition to using a fume cupboard, reflux cooling is also employed. During drying, no further residues must be released from the product.

When wearing gloves, particular attention must be paid to hygiene in order to prevent the spread of contamination.

Stock containers must not be brought into the classroom.

Chemical containers must be transported in carrying aids (buckets, carrying crates, etc.), not by hand or in a lab coat pocket.

The operating instructions and relevant regulations for the school must be observed.

German original

Der Versuch stellt relativ hohe Anforderungen an die experimentellen Fähigkeiten, diese müssen daher vorher vermittelt werden.

Die Freisetzung von Propionsäureanhydrid muss minimiert werden. Daher wird zusätzlich zum Abzug auch unter Rückflusskühlung gearbeitet. Beim Trocknen dürfen keine Rückstande mehr aus dem Produkt frei werden können.

Beim Tragen von Handschuhen ist besonderes Augenmerk auf die Hygiene zu richten, um eine Verschleppung von Kontaminationen zu vermeiden.

Vorratsgebinde werden nicht in den Unterrichtsraum gebracht.

Chemikaliengebinde werden in Tragehilfen (Eimer, Tragekästen etc.) transportiert, nicht in der Hand oder der Kitteltasche.

Die Betriebsanweisungen und einschlägigen Regelungen für die Schule sind zu beachten.
Substitution Substitution 1
The substitution of hazardous substances, as well as forms of use and procedures, has been assessed. The experiment is essential for teaching key learning content and can be carried out provided that the restrictions set out in the experiment protocol are observed and the protective measures specified therein are followed.
There are no known hazardous properties of the substances or other risks that would, in principle, preclude the experiment from being carried out by pupils or teachers. The list of substances in DGUV Information 213-098 at degintu.dguv.de has been taken into account.

Replacing acetic anhydride with propanoic anhydride, whilst maintaining the rest of the process, leads to a reduction in the release behaviour of the starting materials (acid anhydrides) and products (carboxylic acids), leading to a reduction in the risk posed by exposure to corrosive vapours whilst maintaining a comparable GHS/CLP classification). At 20 °C (and correspondingly higher at higher temperatures), the vapour pressure of propanoic anhydride, at less than 2 mbar, is significantly lower than that of acetic anhydride; similarly, the vapour pressure of propionic acid is significantly lower than that of acetic acid (this also applies to the aqueous washing solutions). Given the identical procedures (same apparatus, same durations, same surface areas, same temperatures), it can therefore be estimated that exposure to propionic acid and its anhydride is significantly lower than is the case for propionic acid and propionic anhydride.

Media & figures
Propionylsalicylsaeure_5H.png
Propionylsalicylsaeure_5H.png
Propionylsalicylsaeure_5C.png
Propionylsalicylsaeure_5C.png
Propionylsalicylsäure.png
Propionylsalicylsäure.png

NMR spectra (T.H. Brock et al.): 500 MHz 1H and 125 MHz 13C

Structural formula of propionylsalicylic acid

Literature

T. H. Brock, K. Thieme, BG RCI Leuna Laboratory, nyp

Klemeyer, Horst; Letter to the editor: Quick and cool: ‘Cold synthesis’ of the active ingredient paracetamol in chemistry lessons (2025), https://doi.org/10.1002/ckon.202500026