ethanol

Alcoholic drinks are popular in most of the world. Excessive consumption of them is also a major public health problem. Bans have been attempted, sometimes successfully, sometimes unsuccessfully, but some people argue that alcohol plays a necessary role in social interactions.

Alcoholic drinks contain ethanol, which is metabolized to acetaldehyde, which is metabolized to acetate. In cells, ethanol is mostly unreactive but can bind to receptors. Acetaldehyde reacts with lots of stuff, mostly reversibly but sometimes irreversibly. Small amounts of acetate are essentially irrelevant, mostly providing calories.

Acetaldehyde can inactivate enzymes by causing crosslinking. Large amounts of it are generally bad. We can separate out the effects of ethanol itself and acetaldehyde by looking at people who metabolize acetaldehyde slowly.

About 50% of people of Northeast Asian descent have a dominant mutation in their acetaldehyde dehydrogenase gene, making this enzyme less effective, which causes the alcohol flush reaction, also known as Asian flush syndrome. A similar mutation is found in about 5–10% of blond-haired blue-eyed people of Northern European descent. In these people, acetaldehyde accumulates after drinking alcohol, leading to symptoms of acetaldehyde poisoning, including the characteristic flushing of the skin and increased heart and respiration rates. Other symptoms can include severe abdominal and urinary tract cramping, hot and cold flashes, profuse sweating, and profound malaise. Individuals with deficient acetaldehyde dehydrogenase activity are far less likely to become alcoholics, but seem to be at a greater risk of liver damage, alcohol-induced asthma, and contracting cancers of the oro-pharynx and esophagus due to acetaldehyde overexposure.

— Wikipedia

alternatives to ethanol

Ethanol is what's in drinks because it's produced naturally by a common type of fermentation, it prevents growth of most harmful microbes, and the yeast produced has some nutritional value. But our modern industrial civilization is no longer bound by such prosaic concerns. Can we do better?

ether

Studies, including that of an ether addict in 2003, have shown that ether causes dependence; however, the only symptom observed was a will to consume more ether. No withdrawal symptoms were prevalent.

— Wikipedia

Diethyl ether has the same direct effect as ethanol, but mostly isn't metabolized in the body. Some of it gets metabolized (by a monooxygenase) by oxidation to (ethanol + acetaldehyde), but more of it gets exhaled. Thus, it's similar to what ethanol without acetaldehyde production would be like.

Diethyl ether isn't expensive to make, and there's lots of knowledge about its effects because it was widely consumed in the past. But it does have some problems:

• It's volatile and has a strong smell, so it's obnoxious to other people.
• It has fairly low water solubility, ~6%.
• Above 2% in air, it's inflammable.
• Pure diethyl ether exposed to oxygen can slowly form explosive peroxides.
• It's already been banned most places, and unbanning things might be harder than not banning them.

butanol

At sub-lethal doses, 1-butanol acts as a depressant of the central nervous system, similar to ethanol: one study in rats indicated that the intoxicating potency of 1-butanol is about 6 times higher than that of ethanol, possibly because of its slower transformation by alcohol dehydrogenase.

— Wikipedia

Some butanol occurs naturally in fermented products. Yeasts could be engineered to produce mostly butanol instead of ethanol, but the maximum practical concentration from fermentation is low, ~1%. If it's 6x as effective as ethanol, then 1% would be enough for drinks. It would then provide a similar effect to ethanol with less aldehyde production.

Its boiling point is 118C, and its water solubility is 7%, so it wouldn't evaporate much. The odor is OK, like fruity alcohol, but it's detectable at much lower levels than ethanol. Apparently, the odor is less pleasant at higher concentrations, and hedonically neutral at 300 ppm.

Some naturally occuring microbes produce butanol together with acetone. The acetone could be distilled out relatively easily.

Here's an EPA summary of 1-butanol rat studies. In rats, high doses can cause neurotoxicity and fetal problems. Comparing to mass of ethanol in beer relative to human weight, no problems were found at 0.6 beers/day but some were found at 1.5 beers/day. Considering that 1-butanol has ~6x the apparent intoxicating effect of ethanol in rats, that makes sense if those effects come from the same mechanism as the psychoactive effects of alcohol. However, it's not clear what the rate of (butanal -> butyrate) is in humans compared to (acetaldehyde -> acetate), and if it's proportionately slower, then butanol might not be significantly less problematic than ethanol.

2-methyl-2-butanol

Does this have similar effects to ethanol? Yes, but it's stronger, and some people have been (illegally) using it recreationally.

Since this is a tertiary alcohol (with the oxygen bonded to a carbon with 3 carbons on it) it can't be metabolized by dehydrogenation to an aldehyde, which is one way to avoid aldehyde production. However, that means it lasts too long, leaving people intoxicated for ~2 days. Also, the smell/taste is somewhat bad.

It's worth noting that tertiary alcohols produce the same effect too despite steric issues being plausible.

ethoxyethanol & butoxyethanol

You might think these are safe because they're used in eg some paint solvents, but no, they're somewhat toxic. I wish companies would stop using them in consumer products.

cyclic ethers

We can't use longer hydrocarbons than diethyl ether or butanol because solubility in water gets too low, so how about cyclic ethers?

Would cyclic ethers have the same effect? I'm pretty sure they would. If butanol is stronger than ethanol, and diethyl ether also works, then the mechanism must involve molecules fitting inside a protein hydrophobic pocket with a carboxylic acid group inside it that hydrogen bonds to an ether or alcohol. The effect then probably comes from protein conformational changes from that type of hydrophobic pocket being stabilized. Cyclic ethers would be more conformationally restricted than diethyl ether, yes, but I doubt that would matter here.

Tetrahydrofuran is a 5-member ring, less volatile than diethyl ether and miscible with water, but it's toxic, presumably because it can be metabolized to 1,4 dialdehyde which can react irreversibly in a Paal–Knorr reaction. For the same reasons it's miscible with water, high concentrations also disrupt various biological membranes by acting as a surfactant. It's also somewhat expensive to make, and very flammable, and it has a tendency to form peroxides.

oxane

Oxane is a 6-member ring. 8% solubility in water and a 88 C boiling point are high enough. Like how pentanediol is much safer than butanediol, oxane metabolites are safer than tetrahydrofuran metabolites. The odor is "pungent sweet ethereal".

As it's a bigger molecule than tetrahydrofuran, and pentanediol costs more than butanediol, you might expect this to be more expensive to make, but it's actually cheaper, with 2 practical routes:

• propene + formaldehyde
• -> (dihydropyran + butadiene + butanal) in a Prins + Diels-Alder reaction using solid acid catalyst
• -> dihydropyran hydrogenation

The inputs are very cheap, and those side products are more valuable than the inputs.

• furfural
• -> hydrogenation to tetrahydrofurfuryl alcohol
• -> rearrangement on Al2O3 to dihydropyran
• -> dihydropyran hydrogenation

Furfural is made from biomass, so it's renewable, which I guess is considered good?

I don't want to be like a high school chemistry teacher handling liquid mercury with their bare hands in a classroom to show how it's not absorbed through the skin and all those people afraid of it are just dumb and yes that's a thing that happened. Even asking my dentist to use articaine instead of their usual choice makes me worry I'm overlooking something, which is just silly. But I'm quite confident that pure oxane is safer for humans than ethanol, so I think people should be able to have some high-oxane entertainment if they want. My main concern is that it could last too long; it should be cleared faster than 2-methyl-2-butanol, but because it's less volatile and more soluble than diethyl ether, it wouldn't be exhaled as quickly.

regulations

I think it makes sense for some country with a high rate of alcohol flush reaction to legalize using 1-butanol or oxane as a substitute for ethanol in drinks served at bars and restaurants. If that works out well, people could go from there. However, I'm not sure what would lead to a country doing that...hmm...isn't it a shame that some Japanese salarymen and OLs can't be socially pressured by their bosses into consuming psychoactive substances at company drinking parties merely because they have an adverse reaction? Clearly, this is a societal problem that demands rectification, and if it can't be fixed socially it should be fixed chemically.

Of the above compounds, the one closest to being legal as an alternative to ethanol is definitely butanol. It's allowed as a flavoring in the US; my understanding is, there's no specific limit but usage must be at the lowest level that accomplishes the purpose (of flavoring).

To me, oxane seems like the best ethanol replacement, followed by butanol. As for oxane regulations, it hasn't really been considered by governments at all.

Really, ethanol in drinks is only allowed because it was used historically; I doubt it would be allowed if it was new. If you look at how drugs are handled...in the US, for example, methylphenidate is obligatory for some kids while ethylphenidate is illegal, and they're basically the same but ethylphenidate is probably slightly better.