Ring Flip of glucose

I have recently read about **mutarotation** of glucose specifically


I am familiar with how cyclic structures like **substituted cyclo-hexanes** exist in an equilibrium of **both their chair conformers**.


The thing is, for mutarotation, the interconversion takes place via an open-chain form, which is I think supported by enough experimental evidence like the specific rotation of equilibrium mixture.


[![enter image description here](https://i.stack.imgur.com/9FQpN.jpg)](https://i.stack.imgur.com/9FQpN.jpg)


But, can ring flip take place the old-school way, that is without opening the ring in a solvent like ***CCl4 or Benzene***


Or is the ring too strained to cross the energy barrier?




The short answer is **no**.


* Experiment with a model kit ([example](https://www.maruzen.info/hgs/catalog/product_info.php?products_id=653)) and recognize changing conformers *only* is about wiggling/rotating bonds which may be gradual in many tiny steps.
* The transition from one isomer to an other (e.g., $\alpha{} \rightarrow \beta{}$-glucose) is binary like using a light switch; instead of on/off, it is either (*R*), or (*S*) – or, in case of double bonds, either (*E*), or (*Z*). This requires *breaking* existing/creating new bonds. Solvent, temperature, radiation, pressure, reagents, catalysts may affect the energetic barrier to achieve this, but normally this change requires surpassing a much higher energetic barrier than the typical rotation around a $\ce{C-C}$ single bond.


While simplified,\* this description *often* is sufficient for everyday like chemistry, including your example about the inversion/mutarotation of glucose dissolved in water. In benzene or $\ce{CCl4}$, this reaction however probably will proceed at a much lower rate of conversion than in water because the assumed mechanism includes steps of protonation/deprotonation and these two solvents are not as good "proton shuttles" (as a Bronsted acid/base) as is water.


From a practical perspective, either form of glucose will not dissolve well in benzene, or $\ce{CCl4}$. Mutarotation however is observed for many sugars e.g., permethylated glucose in benzene and surfactants (e.g., described by Fendler *et al.*), or pyridone (e.g., Rony) and still of interest today (e.g., Dujardin *et al.*).


\*) My answer [here](https://chemistry.stackexchange.com/questions/152911/could-gaussian-or-spartan-software-determine-stereoisomers-from-conformational-l/152916#152916) points to some exceptions from this simplification.


**References**


Fendler, E. J.; Fendler, J. H.; Medary, R. T.; Woods, V. A. Catalysis by reversed micelles in non-polar solvents : mutarotation of 2,3,4,6-tetramethyl-α-D-glucose in benzene. *J. Chem. Soc. D* **1971**, 1497–1497; [doi 10.1039/C29710001497](https://doi.org/10.1039/C29710001497).


Rony, P. R. Polyfunctional catalysis. I. Activation parameters for the mutarotation of tetramethyl-D-glucose in benzene. *J. Am. Chem. Soc.* **1968**, *90*, 2824–2831; [doi 10.1021/ja01013a018](https://doi.org/10.1021/ja01013a018).


Dujardin, N.; Dudognon, E.; Willart, J.-F.; Hédoux, A. H; Guinet, Y.; Paccou, L.; Descamps, M. Solid State Mutarotation of Glucose. *J. Phys. Chem. B* **2011**, *115*, 1698–1705; [doi 10.1021/jp109382j](https://doi.org/10.1021/jp109382j).


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