Not to be confused with Pentobarbital, Phenobarbital, or Sodium thiopental. A rather obvious distinction, one would think, for those who bother with specifics.
Pharmaceutical compound
Barbital Clinical Data
| Trade names | Veronal, Medinal AHFS/Drugs.com International Drug Names | | MedlinePlus | a682221 AHFS/Drugs.com International Drug Names Barbital (or, if you prefer, its slightly more archaic cousin, barbitone), was initially released under the brand name Veronal for the pure acid form, and later as Medinal for its soluble sodium salt. It holds the somewhat dubious distinction of being the first commercially available barbiturate. For a period from 1903 until the mid-1950s, it served as a popular solution for the nightly struggle against wakefulness, functioning as a sleeping aid. The more formal chemical nomenclature for this compound includes diethylmalonyl urea or diethylbarbituric acid, which logically leads to its sodium salt being recognized as sodium diethylbarbiturate.
Synthesis
The origin story of Barbital, initially known by its rather poetic trade name "Veronal," traces back to 1902. It was in that year that the illustrious German chemists, Emil Fischer and Joseph von Mering, successfully synthesized this compound. Their groundbreaking findings were subsequently unveiled to the scientific community in 1903, marking a significant milestone in pharmaceutical chemistry.
The primary method for preparing Barbital involved a condensation reaction. This process entailed combining diethylmalonic ester with urea in the discernible presence of sodium ethoxide. Alternatively, one could achieve its synthesis by introducing a minimum of two molar equivalents of ethyl iodide to either the silver salt of malonylurea (barbituric acid) or, more practically, to a basic solution of the acid itself. The culmination of these precise chemical maneuvers yielded an odorless, slightly bitter substance, presenting as a white crystalline powder. Not exactly a feast for the senses, but then, most things that mess with your brain aren't.
This introduction of Barbital was the direct consequence of Fischer and von Mering's meticulous investigations into the pharmacological characteristics of various open and closed acylureas, which at the time were broadly categorized as ureides. Operating under the hypothesis that a significant portion of a compound's hypnotic efficacy was intrinsically linked to the presence of ethyl groups within its molecular structure, they systematically prepared several related compounds. These included diethylacetyl urea, diethylmalonyl urea (which is, as you've no doubt gathered, Barbital itself), and dipropylmalonyl urea.
Their comparative studies revealed intriguing results regarding their sedative potentials. Diethylacetyl urea was found to possess a potency roughly equivalent to sulphonal, a sedative already established in medical practice at the time. The third compound, dipropylmalonyl urea, proved to be remarkably potent, boasting an efficacy four times greater than Barbital. However, its use was plagued by undesirable and protracted after-effects, rendering it less suitable for widespread clinical application. Barbital, in this carefully calibrated spectrum, occupied a middle ground, offering a balance of effectiveness and tolerable side effects, making it a more viable candidate for therapeutic use. A compromise, as ever, is what humanity settles for.
The synthesis of Barbital can also be elegantly achieved through a condensation reaction between urea and diethyl-2,2-diethylmalonate, which is itself a derivative of diethyl malonate. This alternative pathway further underscores the foundational chemical principles employed in its creation.
(image of synthesis diagram would go here)
Marketing
Bottle for "Veronal" crystals, named after the Italian city of Verona, was the first commercially available barbiturate, manufactured by Bayer.
Barbital officially entered the market in 1904, spearheaded by the German pharmaceutical giant Bayer, which branded the pure acid form as "Veronal." Simultaneously, the more soluble sodium salt of Barbital was introduced by Schering under the trade name "Medinal." It was primarily prescribed for the rather broadly defined condition of "insomnia induced by nervous excitability," a charmingly vague diagnosis that allowed for its application to a wide array of restless minds. One might observe that "nervous excitability" could describe the entire human condition.
This new sedative was made available to patients in two forms: as loose crystals or conveniently packaged in capsules. The standard therapeutic dose ranged from ten to fifteen grains, which translates to approximately 0.6 to 1 gram. For context, a mere 3.5 to 4.4 grams (roughly 55 to 68 grains) was generally considered to constitute a lethal dose. The line between therapeutic relief and permanent cessation was, it seems, rather thin. The historical documentation of precise dosages and lethal thresholds from this era is, predictably, less rigorous than modern standards would demand, leading to some retrospective questions regarding the exact figures.
Pharmacology
At the time of its debut, Barbital was hailed as a significant advancement over the existing array of hypnotics. The bar, admittedly, was not set particularly high. Its taste, while described as slightly bitter, was a marked improvement over the notoriously strong and unpleasant flavor of the commonly prescribed bromides. Furthermore, it presented with a relatively low incidence of side effects, and crucially, its therapeutic dose was considered to be comfortably below the threshold of toxicity. A triumph of palatable mediocrity, if you will.
However, the honeymoon period was, as always, fleeting. Prolonged administration of Barbital inevitably led to the development of tolerance in patients, a predictable biological response that necessitated progressively higher doses to achieve the desired sedative effect. This escalating need was famously articulated by the Russian tsarina Alexandra Feodorovna, who, in a candid moment with a friend, lamented, "I'm literally saturated with it." A poignant testament to the drug's insidious grip. The inherent slowness of this particular hypnotic's action also contributed to a disturbingly common occurrence of fatal overdoses, as individuals, seeking more immediate relief, would often consume additional doses before the initial ones had taken full effect. Among the notable figures who tragically succumbed to an accidental overdose of Barbital was the pioneering aviator Arthur Whitten Brown, renowned for his historic "transatlantic flight of Alcock and Brown."
In a more contemporary, and frankly, less lethal development, a photoswitchable derivative of Barbital has been engineered for specialized research applications, falling under the nascent field of photopharmacology. This innovative compound, known as DASA-barbital (a derivative based on a donor-acceptor Stenhouse adduct), exhibits neuronal activity via GABA A receptors and demonstrates reversible photoisomerization when dissolved in water, particularly in the presence of cyclodextrin. It's a rather intricate way to say we're still finding new things to do with old chemicals, often with fewer fatal consequences.
pH buffer
Beyond its primary role as a sedative, solutions of sodium Barbital found an unexpected, yet valuable, application as pH buffers in various domains of biological research. For instance, they were routinely employed in techniques such as immunoelectrophoresis or as integral components within fixative solutions, where precise pH control is paramount for maintaining sample integrity and experimental accuracy.
However, the very efficacy and controlled nature that made Barbital a successful drug ultimately led to its obsolescence in the laboratory. Given its classification as a controlled substance, the logistical and regulatory hurdles associated with its procurement and use in research settings became increasingly cumbersome. Consequently, Barbital-based buffers have, over time, been largely phased out and replaced by alternative, less regulated substances that offer comparable buffering capabilities without the attendant legal complexities. It's almost ironic how its utility across different fields ultimately created its own administrative demise in one of them.
Poisoning
Veronal from Bayer in glass tubes with cork caps - 10 tablets probably produced around 1940
The history of Barbital is inextricably linked to a grim succession of intentional overdoses, serving as a stark reminder of its potent, double-edged nature. In 1927, the acclaimed Japanese writer Ryūnosuke Akutagawa deliberately chose this drug to end his life. Similarly, Pierre Batcheff, an actor famously known for his role in the surrealist film Un Chien Andalou, succumbed to a Barbital overdose in 1932. The Hungarian poet Gyula Juhász followed suit in 1937. The year 1942 saw a cluster of such tragic events: the distinguished German mathematician Felix Hausdorff, the renowned Austrian writer Stefan Zweig (and his wife), and the French Anarchist Germaine Berton all opted for this method of suicide.
Perhaps one of the most harrowing chapters in Barbital's history involves its use during the Holocaust. Faced with the unspeakable horror of imminent deportation to concentration camps by the brutal Nazi Regime, many Jewish residents in cities across Germany, including Berlin, Dresden, and Wiesbaden, made the agonizing decision to take their own lives using "Veronal" as a means to escape a fate worse than death. It was a desperate act of defiance against unimaginable cruelty. Following World War II, Alfred Kerr, a prominent German theatre critic and essayist, suffered a debilitating stroke during a return trip to Germany. In a final act of agency, he chose to end his life via a Veronal overdose, which was sensitively procured for him by his wife.
Beyond self-inflicted tragedies, Barbital also featured in a notorious criminal case. Eric Mareo, the son of playwright Raimund Pechotsch, was implicated in the murder of his wife, Thelma, using Veronal. A key witness in the ensuing trial was Thelma's lesbian lover, Freda Stark, whose testimony added another layer of complexity to the already sensational proceedings. The drug's capacity for destruction, it seems, was not limited to self-harm.
In fiction
The pervasive influence of Barbital extended beyond the clinical and historical records, seeping into the realm of popular culture and fiction. In D. H. Lawrence's poignant story, The Lovely Lady, the eponymous character ultimately meets her demise through a self-administered overdose of the drug, illustrating its thematic power as a tool of escape.
Barbital, frequently under its well-known brand name Veronal, also served as a recurring and effective plot device in the intricate murder mysteries penned by the celebrated author Agatha Christie. Its quiet lethality made it an ideal instrument for fictional foul play.
Furthermore, its dramatic potential was recognized in the burgeoning medium of television, with Barbital being utilized as a crucial plot element in an episode of the CBS legal drama, Perry Mason, specifically in "The Case of the Missing Element," which aired in 1963.
Even in the sprawling post-apocalyptic narrative of Stephen King’s The Stand, Barbital makes an appearance as a method of suicide. A character named Perion chooses this means to end her life after the tragic death of her partner, Mark, from appendicitis, underscoring its enduring association with finality in the face of despair. It seems even in fictional universes, humans find the same old ways to check out.