Very Cool Compounds

Just as there are molecules that make your tongue tingle, there's a class of compounds that create a cooling sensation. Why, you might ask, would major companies all over the world invest lots of time and money into creating chemicals that simply make your skin or tongue feel cold?

 First, there's a perception among consumers that coolness equates to freshness and cleanliness so the appeal of these characteristics in personal hygiene products like toothpaste, shampoo, shaving cream, etc. is high. Consumers want gum, medicines, breath fresheners, and more that cool without being bitter, burning, stinging or tingling.

Secondly, flavor and fragrance companies are seeking less expensive means of creating this popular refreshing sensation, so a number of both natural and synthetic molecules have come "on the market." The more "natural" a chemical is the better: it's appealing to consumers and often less complicated to make. Cheaper production of either, however, allows flavor and fragrance businesses to compete with each other for contracts to industrial producers.

Finally, research is being done to find out which cooling compounds work synergistically with other ingredients to enhance or alter products for desired traits. A number of new cooling compounds have been created as a result of this research that also work as stand-alone cooling agents.

There is a wide variety of cooling products.

The two most important traits of a cooling compound are duration and intensity. The best ratio of these traits varies depending on the product. A minty gum, for instance, might require a burst of flavor when initially bitten but maintain a refreshing feel as long as it's being chewed. A body spray, on the other hand, might be intended to make the skin feel slightly cleaner at the moment of contact (versus oily or dirty).

The many different uses of cooling compounds makes the chemistry tricky. The amount of menthol needed to make the gum seem to burst with flavor would likely go unnoticed on the skin because cells in the mouth, and thus nerves, are more nearly exposed. Likewise, the amount of a cooling agent used to make the skin feel fresh would probably be bitter and disgusting if used in a piece of gum.

In general, cooling compounds have a hydrogen bonding group, a compact hydrocarbon skeleton, both hydrophilic and hydrophobic structural components, and a molecular weight between 150 and 350g/mol. Certainly, the hydrogen bonding and lipophilicity are the two most crucial components of a cooling agent. The industry's favorites have h-bonding groups that are hydroxy, n-alkyl carboxamides (for rapid cooling), sulfides, and phosphine oxides.

Carboxamide Functional Group

The lipophilicity is crucial as many cooling components are added to the flavor or fragrance oil and mixed before other ingredients are added. Since many liquid products such as sodas or alcoholic beverages contain theses chemicals, it's important that the cooling agent is in an easily miscible vehicle to prevent separation.

Hydrogen Bonding in Water

There are many, many of these cooling compounds so I'll detail just a few to give you an idea of the chemistry behind their design and the desired properties that they fulfill. 

Menthol and its direct derivatives are among the most common and oldest cooling compounds because of their "natural" sources in peppermint and cornmint oils. Although the naturally derived menthol is subject to price fluctuation due to crop success, it's still usually cheaper than fully synthetic menthol. Interestingly, the L-enantionmers are up to 45X more active than their D-menthol counterparts and the cooling effects of L-menthol can be detected on the skin in a solution with less than a 1% concentration.  Even at as low as 2%, the effects of menthol become "anesthetic" or "irritating" and at greater than 0.3 micrograms, say, in a piece of gum, it is irritating to cells in the mouth.

L-menthol is a ~45x more active cooling agent. 

Flavor and fragrance companies take potent and common chemicals such as menthol and toy around with them, hoping to achieve something more marketable. Takasago, for example, used the highly purified menthol isomer L-(-)-Isopulegol to make a specialty ingredient that "provides freshness, crispness, and coolness to citrus fragrances."They renamed it "Coolant P," a practice common throughout the industry to simplify long and often structurally confusing IUPAC names. The author says of one popular carboxamide:

“When called by its chemical name the structure is confusing, indeed a rather more sane chemical name would be N-methyl 2-isopropyl-2,3-dimethyl propionamide. In any event, it is sold by some companies as WS-23…” (p.219). 

Sometimes chemicals will be developed for specific industry purposes, such as the completely synthetic L-Monomenthyl  succinate. First reported by the British American Tobacco Co. in 1962 for use in manufacturing tobacco, this cooling agent was reported again in 1965 as a flavoring agent in cigarettes. The tobacco industry found this chemical desirable and worth further research because it is easily synthesized by a reaction of menthol with succinic anhydride. Its addition to cigarettes makes them taste less disgusting, presumably, and is intended to leave the smoker's mouth feeling…clean? 

Other cooling compounds are designed without a specific product in mind, but rather for their appeal to consumers as an ingredient. L-(-)-Monomenthyl glutarate, a.k.a. “Cooler 2," is "nature identical" meaning that it's exactly the same as a natural product, just created in a lab. International Flavors and Fragrances markets this as just that - nature identical - because the designation funnily enough lies in slightly higher esteem than "synthetic." 

There are a few cooling compounds that I recall actually having seen on ingredients labels before: mannitol, sorbitol, urea, methyl salicylate and camphor. Though not related to menthol, these compounds all have a sweet cooling character. What's really cool is that in mannitol, urea and sorbitol this effect is achieved through heat of dissolution. So, it's not just your brain being tricked into thinking it feels cooler, but there's an actual heat exchange occurring over the surface of the cell. Pretty neat.

The final category is what I like to think of as experimental cooling compounds. These are things that aren't actually on the market because they're potentially not safe or not perfected. AG-3-5 or "Icilin" is one such compound. Although it's a very potent cooling agent that is reported to create a refreshing sensation from the mouth all the way to the stomach, it's also a suspected mutagen. No big deal.

In short, there are a lot of cooling compounds used for a variety of business and chemical reasons. So, next time you're chewing a piece of gum, try to mentally separate the cool, refreshing feeling from the flavor itself. It's a pretty cool exercise and something I hadn't thought about before. Plugging your nose while taking the initial chews also helps make this distinction - you'll notice that your mouth feels cool and clean without experiencing the mintiness to the same degree. And there are actually panels of scientists who decide which cooling compounds achieve this sensation most successfully! What a job.

Next time on the Taste of Chemistry: Warming Compounds!

Ashley

Speaking of stinky breath: Bonus Video!

 





1 Rowe, David J (ed.) (2005) Chemistry and Technology of Flavors and Fragrances. Blackwell Publishing: Poole. Ch.9.^↩

The Tingle Factor

Yes, this sounds a bit strange at first.

There's a whole industry around "tingle compounds" - molecules that make prickly and numbing sensations on the mouth, teeth, lips, tongue, and throat. These compounds have been described to feel like everything from a mild anesthetic to a nine-volt battery being attached to the tongue. The flavor and fragrance industry has a lot of reasons to research and develop new such substances as they:

•  strengthen carbonation and alcoholic strength
• enhance cooling, warming and sweetness
• can feel refreshing and cleansing 
• have anti-microbial properties
• good marketing as skin soothing (think: tea tree shampoo)

When a substance comes in contact with the body it's received in one way or another by nerves and receptors that help tell the brain what chemical it has just encountered. "The Common Chemical Sense" is a way to describe how the body "perceives" or "feels" irritating chemicals. And, on a side note, irritating here doesn't necessarily mean annoying it just means that when certain molecules hit corresponding receptors it causes a sensation that is not a taste. In the context of flavor and fragrance chemistry these encounters with substances are detected through "chemesthesis" (i.e. chem for chemical and esthesis for recognizing that something is there).

The mechanism by which tingle compounds are experienced is a bit complicated but it goes something like this:

1. Gum, toothpaste, salsa, mouthwash, whatever (thing with tingle compound) is consumed.
2. Consumable comes in contact with cells inside and around the mouth. You may recall from a biology class that cells have a membrane that doesn't let just anything through - it's selective. Only compounds with the right composition are allowed through the semi-permeable phospholipid bilayer. Things that dissolve in lipids can pass through this barrier because "like dissolves like." 
3.  Fortunately for Altoid-lovers, active tingle compounds pass through cell membranes because scientists and/or nature have cleverly designed them with a hydrophobic structural component that allows it to be soluble in lipids and to reach nerve endings.
4. The tingle compound binds with the nerve/receptor and a signal is sent to the brain that is translated to a sensation because scientists and/or nature also put a hydrophilic functional group on the molecule.
5.  Summary: tingle compounds are able to pass through the lipid and aqueous layers of cell membranes and from there come in contact with those trigeminal nerve endings. 

If you need some background on cells, go ahead and give this a watch: 

There is a wide variety of structures that create a tingling sensation because the molecules are generally very flexible and therefore have many spatial conformations (i.e. they can bend, twist, etc.). Although the structure-activity relationship of tingle compounds is not well understood, there are a few generalizations that can be made based on the juxtaposition of compounds that create this sensation and those that do not. In order to be active, tingle compounds:

• must have an amide functional group attached to a conjugated double bond but separated by at least two carbons from any non-conjugated double bonds
• a second double bond that either continues the conjugation or is a z-double bond 
• R and R' groups that are sufficiently polar for mucous-membrane crossings
• plus some additional bonds here and there

Hydroxy-Alpha-Sanshool
(Wikimedia Commons)

So, a little confusing and unspecific but better than nothing in terms of future syntheses of new compounds. Why, one might ask, would industry be so invested in creating new tingle compounds? 

Surprisingly, the use of such chemicals as additives to flavors of gum, mouthwash, mints, candy, beverages, toothpaste and more is projected to increase. 

New and better synthetic tingle compounds might cause a consumer to pick one toothpaste over another. The research is focused on removing “negative” qualities from natural products which include taste, pungency, saltiness, limited aqueous solubility, and instability that is associated with natural extracts. Fully synthetic compounds are preferred by scientists because there is no reliance on a crop and in a lab setting purity, concentration solubility, stability, and flavor are easily controlled. 

"Natural and Artificial Flavors"

 Wikimedia Commons

Here's an interesting observation: synthetic tingle compounds have scary names like N-Isobutyl E,E,Z-2,4,8-undecatrienamide and N-isobutyl dodecatetraenamide (tetrahydro-alpha-sanshool). With a growing demand for "ingredients you can pronounce" companies must surely be vying for their right to put "artificial flavoring" on their labels and leave it at that. 

Echinacea Flower 

Wikimedia Commons

There are a few oft-used natural products that produce a tingling sensation. These include spilanthol, sanshool, isoaffinin, and pellitorine. In common English, those translate to toothache plant (properties of which were discovered by Gerber in 1903), Szechuan peppers, mount atlas daisy, and regular old black pepper. The uses of these compounds span the same range as the synthetic ones - spilanthol is added to spirits, sanshool occurs in echinacea, yarrow root tea contains isoaffinin, and pellitorine might just be responsible for that fresh clean feel you get from chewing certain brands of gum. 

Ashley

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1 Rowe, David J (ed.) (2005) Chemistry and Technology of Flavors and Fragrances. Blackwell Publishing: Poole. Ch.9.^↩

Taste and Sensation (To be continued….)

Most people are pretty comfortable with our sense of taste - we've got taste buds that let us experience the salty, bitter, sweet, sour and umami characteristics of food. And that's pretty much it, right? That's how we taste our food, end of story.

Eh, not so much as it turns out. There are whole lot of other factors that play into how we experience what we eat. The most important thing is likely taking into account that our sense of smell contributes significantly to how we experience flavor. But that's just scraping the surface.

Have you ever wondered about the cool freshness from a piece of mint gum? How about the spiciness of a jar of salsa? Those aren't quite smells or tastes, are they? There's actually a whole area behind the mouth that's full of nerves that communicate sensations like tingling, warmth, and even pain to brain.

Ever burned your tongue? There are areas all over your mouth, esophagus, and even larynx that lack taste buds but have these sensing fibers that send that "ouch I burned my tongue on something hot" message despite the fact that this feeling has nothing to do with taste.

The nerves responsible for these additional sensations that have nothing to do with taste or smell are called the Trigeminal Nerve System. This is the largest cranial nerve is the primary nerve responsible for taste and sensation in the face and the motor nerve for chewing. Pain, mouthfeel, temperature, tingling, prickling, and multiple sensations at once (polymodal) are all results of receptors in this nerve system. 

These nerves affect the face and head in three zones, shown in the picture below. Clearly, these sensations expand far beyond the tongue. 

Three Trigeminal Areas
(Wikimedia Commons)

In the next post, I'll go into detail on the compounds that are used to create these non-flavors. 

Ashley

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1 Rowe, David J (ed.) (2005) Chemistry and Technology of Flavors and Fragrances. Blackwell Publishing: Poole. Ch.9 pp199-205.

What is Flavor and Fragrance Chemistry?

People have always loved smelling nice and eating nice tasting foods. From perfumes in ancient Egypt to the first synthesis of vanillin from coniferin in 1874, imitating nature or inventing bizarre flavors and fragrances is as much a part of human history as it is a scientific enterprise1. This blog will focus on conventional chemical knowledge in this field, including synthesis, chemical compositions, sensory effects, and manufacturing processes as well as emerging sustainable technologies such as biocatalysts, genetic engineering, and cell cultures.

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1 Berger, R.G. (ed.) (2007) Flavours and Fragrances: Chemistry, bioprocessing and sustainability, Springer: Heidelberg.