The researchers attempted to synthesize D and L mannose using furfural and a Grignard reaction but were unsuccessful in obtaining a significant yield of the desired product. They conducted several trials varying parameters such as reagents, solvents, temperatures, and ensuring dry reagents. In one trial using furfural, Grignard reagent, and refluxing THF, an unexpected 11 carbon product was formed that was identified as (E)-1,3-di(furan-2-yl)prop-2-en-1-one through NMR, mass spectrometry, and IR spectroscopy matching literature values. A mechanism was proposed to explain the formation of this product. Overall, the Grignard reaction of fur

1. Furfural to ẞ-hydroxy Silane Grignard Reaction
Joseph Da, Yasin Mohamed, Sathwik Katragadda, Viren Lad, Eric A. Hill, Ph.D.
Johns Hopkins University
1. Harris, Joel M.; Keranen, Mark D.; O’Doherty, George A. Syntheses of D- and L-Mannose, Gulose, and Talose via Diastereoselective and Enantioselective Dihydroxylation Reactions. J. Org. Chem. 1999, 64, 2982-2983.
1. Sharpless, K. B.; Amberg, W.; Bennai, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-Z. J. Org. Chem. 1992, 57, 2768.
1. Wei, L; et al. Design, Synthesis and Antifungal Activity of a Series of Novel Analogs Based on Diphenyl Ketones. Chemical Biology & Drug Design. 2009, 73, 661-667.
References
We intended to conduct the synthesis of D and L mannose using
the Harris procedure. However, in the first step of the synthesis,
the Grignard reaction with furfural did not produce a significant
amount of product. We then turned our focus to investigating the
reasons behind this issue by altering solvents, temperature,
reagent ratios, and reagents. Hence, our trials investigated the
conversion of furfural to ß-hydroxy silane through a Grignard
reaction or to vinyl furan through a Wittig reaction. Several
experiments were done to test the purity of the starting materials
as well. Following the trial runs, we were unable to form the
intended product to an appreciable extent and also formed an
eleven carbon structure. With the formation of this unexpected
product, a mechanism was also proposed.
Abstract
Introduction
In our synthesis of B-hydroxy silane, the majority of the reactions were carried
out under nitrogen. In order to limit exposure to air or water, hot glassware
was taken directly from the oven and purged with nitrogen three times with
our Schlenk line setup. All reagents were added by syringe, dropwise initially,
and then normally until desired amount was added. While the reaction was
running, we took periodic TLCs to assess the progress of the reaction. After the
reaction ran to completion, it was quenched with concentrated ammonium
chloride, and a series of extractions were performed with sodium bicarbonate
and brine. The resulting product was gravity filtered, and the product was
submitted for 1H NMR. The series of conducted trials can are listed below:
In trial 1, we added TMSCH2MgCl (Grignard reagent) (1.2 eq.) to furfural (1 eq.)
in anhydrous diethyl ether.
In trial 2, furfural (1 eq.) was added to Grignard reagent (1.2 eq.) in anhydrous
diethyl ether.
In trial 3, furfural (1 eq.) was added to Grignard reagent (3 eq.) in anhydrous
THF, and set to reflux as well. After extractions and recrystallizations, an 11
carbon product was made.
In trial 4, a Wittig reaction was run with furfural (1 eq.) and PPh3CH2(3 eq.) in
anhydrous THF with catalytic amounts of potassium tert-butoxide.
In trial 5, benzaldehyde (1 eq.) was used with our Grignard reagent (3 eq.) in
anhydrous diethyl ether.
In trial 6, distilled furfural (1 eq.) was added to Grignard reagent (1.2 eq.) in
anhydrous diethyl ether.
In trial 7, distilled furfural (1 eq.) was added to Grignard reagent (3 eq.) in
anhydrous THF.
Methods and Materials
The Grignard reaction of furfural posed a major obstacle in the
synthesis of mannose. Even with inert conditions, and after
changing reagent ratios, temperature, and ensuring that the
furfural itself was dry, we were not able to match literature yields
of ẞ-hydroxy silane3 (90%).
In regards to trial 3’, our formed 11 carbon product match
literature reported values in terms of 1H NMR, 13C NMR. In addition,
the mass of (E)-1,3-di(furan-2-yl)prop-2-en-1-one matches our mass
spectrometry data. Moreover, the carbonyl peak on our IR
spectrum matches the structure.
Because our product matches the spectra of (E)-1,3-di(furan-2-
yl)prop-2-en-1-one, a mechanism was proposed in which it was
assumed that the pKa of Si- is acceptable. If this mechanism is true,
it presents an exception to the beta-silicon effect.
Discussion
After completion of all of our Grignard and Wittig reaction trials, we
were unable to synthesize the product we wanted to a significant
extent. In our trials we tried a variety of reagents, and solvents.
Despite minor product synthesis, running a Grignard reaction under
classroom laboratory conditions faces several hindrances. However,
the formation of the eleven carbon structure under reflux and THF
conditions allowed for a possible reaction mechanism. We would
like to continue to explore this reaction especially with kinetic
studies. We also hope to explore Grignard reactions in greater
depth and conduct a successful reaction with appreciable yield.
Conclusion
Results
Mechanism 1. Proposed pathway for Trial 3’. Conversion of furfural to (E)-1,3-di(furan-
2-yl)prop-2-en-1-one
Joel Harris and other scientists synthesized D and L mannose from
furfural using a Grignard reaction and Upjohn dihydroxylation
conditions. Dihydroxylation is the reaction in which an alkene is
converted to vicinal diols. Using certain reagents, it possible to form
specific enantiomers from dihydroxylation. In Intermediate Organic
Chemistry Laboratory, students performed a Sharpless Asymmetric
Dihydroxylation or SAD in order to generate an excess of one
enantiomer.
The Grignard reaction is an organometallic reaction in which usually
magnesium halides react with carbonyl groups. These reagents are
useful for the formation of carbon-carbon bonds. However, these
reactions are usually very exothermic and react adversely with
water. In our experiment, we attempted to run mannose synthesis
under classroom laboratory conditions. However, as stated above,
the first synthesis step did not result in an appreciable yield. Hence,
the experiment was altered to focus on the Grignard reaction.
Image 1. Distillation Apparatus Image 2. Schlenk Line
Trial 1 (Grignard reagent to furfural): 1.15% yield*.
Trial 2 (furfural to Grignard reagent): 5.61% yield*.
Trial 3 (3:1 Grignard reagent:furfural, reflux): 7.70% yield*.
Trial 3’ (after filtrations, recrystallizations): 1.3% yield.
1H NMR (Literature values3 are in standard font, experimental values bolded) (in
ppm):
6.52 (quartet), 6.51 (quartet); 6.59 (quartet), 6.58 (quartet); 6.73 (doublet),
6.73 (doublet); 7.31 (doublet), 7.31 (doublet); 7.32 (doublet), 7.32 (doublet);
7.54 (doublet), 7.53 (doublet); 7.63 (doublet); 7.62 (singlet), 7.65 (singlet)
13C NMR (Literature values3 are in standard font, experimental values bolded)
(in ppm):
177.74, 177.7; 153.74, 153.7; 151.6, 151.6; 146.52, 146.6; 145.01, 145.0;
129.86, 129.9; 118.89, 118.8; 117.36, 117.4; 116.32, 116.4; 112.69, 112.7;
112.47, 112.5
Mass spectrometry:
Base peak: 189 M/z, M of (E)-1,3-di(furan-2-yl)prop-2-en-1-one = 188 g/mol.
Infrared spectroscopy:
Carbonyl peak at 1653.97 cm-1.
Trial 4 (Wittig reaction): 0% yield*.
Trial 5 (Grignard reaction of benzaldehyde): 136.34% yield*.
Trial 6 (distilled furfural): 33.39% yield*.
Trial 7 (distilled furfural, 3:1 Grignard reagent:furfural, reflux): -.
Note: * denotes a crude yield, with the assumption that other impurities in the product are
nonexistent.
Acknowledgments
We would like to thank Dr. Hill, as well as the TAs: Heidi, Eric,
Michael, Levi, and Hunter, for spending an immense amount
of time in lab, and helping us with all facets of our special
project.