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.^↩