title: Tipson–Cohen reaction
text: # Tipson–Cohen reaction
  
  The Tipson–Cohen reaction is a name reaction first discovered by Stuart Tipson and Alex Cohen at the National Bureau of Standards in Washington D.C. The Tipson–Cohen reaction occurs when two neighboring secondary sulfonyloxy groups in a sugar molecule are treated with zinc dust (Zn) and sodium iodide (NaI) in a refluxing solvent such as N,N-dimethylformamide (DMF) to give an unsaturated carbohydrate.
  
  ## Background
  
  Unsaturated carbohydrates are desired as they are versatile building blocks that can be used in a variety of reactions. For example, they can be used as intermediates in the synthesis of natural products, or as dienophiles in the Diels-Alder reaction, or as precursors in the synthesis of oligosaccharides. The Tipson–Cohen reaction goes through a syn or anti elimination mechanism to produce an alkene in high to moderate yields. The reaction depends on the neighboring substituents. A mechanism for glucopyranosides and mannooyranosides is shown below.
  
  Scheme 1: Syn elimination occurs with the glucopyranosides. Galactopyranosides follows a similar syn mechanism. Whereas, anti elimination occurs with mannopyranosides. Note that R could be a methanesulfonyl $CH_2O_2S$ (Ms), or a toluenesulfonyl $CH_3C_6H_4O_2S$ (Ts).
  
  ## Reaction mechanism
  
  Scheme 3: The scheme illustrates the first displacement, the rate determining step and slowest step, where the starting material is converted to the iodo-intermediate. The intermediate is not detectable as it is rapidly converted to the unsaturated sugar. Experiments with azide instead of the iodide confirmed attack occurs at the C-3 as nitrogen-intermediates were isolated. The order of reactivity from most reactive to least reactive is: β-glucopyranosides > β-mannopyranosides > α-glucopyranosides> α-mannopyranosides.
  
  The reaction of β–mannopyranosides gives low yields and required longer reaction times than with β-glucopyranosides due to the presence of a neighboring axial substituent (sulfonyloxy) relative to C-3 sulfonyloxy group in the starting material. The axial substituent increases the steric interactions in the transition state, causing unfavorable eclipsing of the two sulfonyloxy groups. α-Glucopyranosides possess a β-trans-axial substituent relative to C-3 sulfonyloxy (anomeric $OCH_3$ group) in the starting material. The β-trans-axial substituent influences the transition state by also causing an unfavorable steric interaction between the two groups. In the case of α-mannopyranosides, both a neighboring axial substituent (2-sulfonyloxy group) and a β-trans-axial substituent (anomeric $OCH_3$ group) are present, therefore significantly increasing the reaction time and decreasing the yield.
  
  ## Reaction conditions
  
  Table 1: Reaction times and yield vary on the substrate. The β-glucopyranoside was found to be the best substrate for the Tipson–Cohen reaction as the reaction time and yield were much superior that any other substrate proposed in the study.
  
  | $Substrate^a$ | Time (hours) | Yield (%) |
  | - | - | - |
  | β-glucopyranoside | 0.5 | 85 |
  | β-mannopyranoside | 2.5 | 66 |
  | α-glucopyranoside | 12 | 55 |
  | α-mannopyranoside | 15 | 10 |
  
  $^aSubstrates$ possess benzylidene protecting groups at C-4 and C-6, OMe groups at anomeric position and OTs groups at C-2 and C-3. Reaction temperature 95–100 ˚C
  
  ## Reaction scope
  
  * The reaction has been attempted in the microwave, improving yields with the α-glucopyranoside to 88% and reducing the reaction time significantly to 14 minutes.
  * The original paper by Tipson and Cohen also used acyclic sugars to illustrate the utility of the reaction. Thus the reaction is not limited to cyclic carbohydrate derivatives.
  * Sulphonoxy groups such as methanesulfonyl and toluenesulfonyl were both used, however it was found that substrates with toluenesulfonyl groups gave higher yields and lower reaction times.
  