Reacción de Bulterow

TetrahedronLetters No. 21, pp. 22-26, 1959.Pergemon Press Ltd.
Printed in
Great Rritain.
ON THE WRCRANISM OF THE FORMOSE FBACTION
Ronald Rreslow
Dept. of Chemistry,Columbia University,.NewYork, N. Y.
(Reoeived25 November 1959)
IN 1861 Butlerowl first noted the formation of sugar-likesubstanceswhen
formaldehydeis treated with mild base. Since that time numerous investi-
gations of this reaction have been undertaken,2and many mechenismihave
been suggested for the process, but to date no mechanism appears to have
been formulatedwhiah does not employ "active formaldebydewor some other
ill-definedspecies. It is the purpose of this communicationto aall
attention to the considerablebody of data available on this reaction
to point out a mechaniem which is consistentwith such data and which iS
also consistentwith chemical experience.
Although a heterogeneousmixture of products ia usually obtained on
treatment of formaldehydesolutionswith base, conditionshave been realized
in which as much as 5& of the original formaldehydehas been oonverted to
glyoolaldehyde,3 Furthermore,trioeea, tetroses,eto., aould easily arise
1
A. Butleroa, C. R. Aced. Soi., Paris 22, 145 (1861).
2
For a short review with leading referenoes,cf. W. Langenbeck,
Tetrahedron2, 185 (1958).
3 W, Langenbeck,Angen. Chem, 66, 151 (1954).
22
No.21 Cn the mechanism of the formose reaction 23
from aldol condensationsinvolvingglycolaldehydeas the active methylene
componentsnd formaldehyde,glycolaldehyde,etc., as the csrbonyl component.
For this reason it has long been obvious that the formation of glycolal-
dehyde from formaldehydeis the process to be explained,and we will not
further consider the subsequentcondensationreactions in this paper.
The reaction of two formaldehydemolecules by an "aldo condensation8V
mechanism is of course very unlikely, and the finding that there is a long
inductionperiod in the formose reaction4 suggests that if such a direct
process does occur it must be very slow. However, kinetic studies have
shown that after this induction period a rapid reaction ensues.4 This
suggests sn autocatalyticprocess, and this has been confirmedby the
finding that the addition of glyoolaldehyde,glyceraldehyde,or dihydroq-
acetone causes the inductionperiod to disappear, the reaction starting
immediatelybut at the ssme rate as that observed in the fast part of the
normal formcse reaction. This has led to the suggestionthat there are
two processes by which the formaldehydecondensationoccurs: (1) a slow
direct condensation,possibly involving a formyl anion, but forming
glyoolaldebydeat an indetectablerate. (2) a fast reaction, catalysedby
glycolaldehyde,.inwhich formaldehydecondenses to a second molecule of
glycolaldehyde.
The first reaotion is certainly interesting,but it is relatively
inacessiblefor study if it proceeds at an indetectablerate, and if the
rate is slow the reaction is not inconceivableas formulated,being related
4 Careful kinetic studies, with references to the earlier work, are

reported by E. Pfeil.and G, Schroth,& iz, 293 (1952).
24 On the meohanism of the formose reaction No.21
to other oases in whioh some moderate aoidity of hydrogens on a double bond
has been observed.5 The high rate of the second process strongly indioates,
however, that some more usual types of reaction are involved in its
mechanism. We wish to point out that, although minor modificationsin
details are possible, the following series of simple oondensationsand
tautomerizationssuffioe to rationalizethe process:
(1) 'XI20+ HOCH2-CHO _3 HOCH2-CHOH-CHO
(2) HOCH2-CHOH-CHO ,- HOCH2-CO-CH20H
(3) CH20 + HOCH2-CO-CH20H + HOCH2-CHOH-CO-CH2OR
(4) HOCH2-CHOH-CO-CH20H \d HOCH2-CHOH-CHOH-CHO
(5) HOCH2-CHOH-CHOH-CHO __+ HOCH2-CHO + HOCH2-CHO
The first aldol oondensationis unexoeptionable,and the tautcmerizationof
glyoeraldehydeto dihydroxyacetonethrough the common enol is also well
hOWIl. This osn of course undergo a second aldol condensationto form the
keto tetrose. The crucial step is the next one, in which this keto l&rose
tautomerizesto the aldotetrose. This is simply the aldol oondensation
, and by a simple reverse aldol reaction oan

product of two glyoolaldehydes
regenerate the original glyoolaldehydeand liberate the new one, which has
thus been synthesizedfrom two formaldehydemoleoules.
This mechanism is oertainlyoonsistentwith the operation of small
amounts of glycolaldehyde,glyoeraldehyde,or dihydroqacetone in
eliminatingthe induction period but not affecting the rate of the fast
process, assuming that a steady state oonoentrationof these intermediates
would be establishedbecause of the competing further condensations.
5 R. Rreslow, J. Amer. Chem. Soo, SO, 3719 (1958).

No.21 On the meohaniam of the formoae reaction 25
-thermore, this mechanism explains why benzoylcarbinolcan give both an
immediatereaction and a faster reaction when it is added as catalyst to
the formaldehydereaction mixtures3 for it oan function in place of
glycolaldehyde,thus eliminatingthe induction period, and condensation
reactiona involving benzoylcarbinolmight zell be even faster than those
involving glycolaldehyde,a presumptionwhich is supported by the obeer-
vation that m- and p-cyanobenzoyloarbinol

are etill better catalysts,while
the p-methoxy compound ia somewhat worae.
Many other catalysts are known for this reaction,2and moat of them,
e.g. benzoin, could not function in place of glycolaldehydein our
mechanism,a factor which has undoubtedly contributedto the overlookingof
this mechanism previously. However, in all these cases the effect is to
shorten the induction period only, and the eventual reaction rate is not
accelerated,but is identicalwith that in the fast part of the normal
reaction. Thus we suggest that many of these other catalysts facilitate
the formation of the first molecule of glyoolaldehyde,but that the catalysts
are not involved in the fast section of the reaction. It is possible to
suggest reasonablemechanism for all of these cases by which the first
glycolaldehydemolecule might be produced more rapidly, but these will not
be outlined here since our prime concern is with the second fast part of
the reaction.
It has also been found that the reaction ia very dependent on the
metal ion involved in the baae,5 being rapid with thallium or lead hydroxides,
relatively fast with calcium hydroxide, and of negligible importancewith
sodium or potaeaium hydroxide. It haa even been found that in the presence
of an appropriatemetal ion the reaction can be acid catalyzed. All of this

26 On the mechanism of the formose reaction No.21
is explicable in terms of the well known stabilizingeffect of chelating
ions on enediols,nhich are postulatedintermediatesin the tautomerisation
and condensationsteps of our mechanism. Finally, the uniqueness of

.
formaldehydein this reaotion derives from the fact that i.2alone among the
aldehydes can oondense to an acyloin with an active mathylene group, snd
therefore,it alone can lead to an autooatalyticreaction.
The function of glycolaldehydein this mechanism is clearly analogous
to that of cysnide ion in the benzoin condensation. A oarbonionis
involved (in this case the enolate ion of glyoolaldehyde)whose carbon also
has aarbonyl-likecharaoter (in this case by tautomerisationto a true
carbonyl group). The prediationof other catalysesof this type and some
other prediotionsbaaed on our suggestedmechanism are currentlyunder
investigation.

Reacción de Bulterow

Uploaded by

Copyright:

Available Formats

Reacción de Bulterow

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Reacción de Bulterow

Uploaded by

Copyright:

Available Formats

TetrahedronLetters No. 21, pp. 22-26, 1959.Pergemon Press Ltd.

ON THE WRCRANISM OF THE FORMOSE FBACTION

Dept. of Chemistry,Columbia University,.NewYork, N. Y.

(Reoeived25 November 1959)

IN 1861 Butlerowl first noted the formation of sugar-likesubstanceswhen

gations of this reaction have been undertaken,2and many mechenismihave

been formulatedwhiah does not employ "active formaldebydewor some other

ill-definedspecies. It is the purpose of this communicationto aall

attention to the considerablebody of data available on this reaction

to point out a mechaniem which is consistentwith such data and which iS

also consistentwith chemical experience.

Although a heterogeneousmixture of products ia usually obtained on

treatment of formaldehydesolutionswith base, conditionshave been realized

in which as much as 5& of the original formaldehydehas been oonverted to

glyoolaldehyde,3 Furthermore,trioeea, tetroses,eto., aould easily arise

from aldol condensationsinvolvingglycolaldehydeas the active methylene

componentsnd formaldehyde,glycolaldehyde,etc., as the csrbonyl component.

dehyde from formaldehydeis the process to be explained,and we will not

further consider the subsequentcondensationreactions in this paper.

The reaction of two formaldehydemolecules by an "aldo condensation8V

inductionperiod in the formose reaction4 suggests that if such a direct

suggests sn autocatalyticprocess, and this has been confirmedby the

finding that the addition of glyoolaldehyde,glyceraldehyde,or dihydroq-

acetone causes the inductionperiod to disappear, the reaction starting

two processes by which the formaldehydecondensationoccurs: (1) a slow

direct condensation,possibly involving a formyl anion, but forming

glyoolaldebydeat an indetectablerate. (2) a fast reaction, catalysedby

glycolaldehyde,.inwhich formaldehydecondenses to a second molecule of

The first reaotion is certainly interesting,but it is relatively

inacessiblefor study if it proceeds at an indetectablerate, and if the

rate is slow the reaction is not inconceivableas formulated,being related

4 Careful kinetic studies, with references to the earlier work, are

to other oases in whioh some moderate aoidity of hydrogens on a double bond

mechanism. We wish to point out that, although minor modificationsin

details are possible, the following series of simple oondensationsand

tautomerizationssuffioe to rationalizethe process:

(1) 'XI20+ HOCH2-CHO _3 HOCH2-CHOH-CHO

(2) HOCH2-CHOH-CHO ,- HOCH2-CO-CH20H

(3) CH20 + HOCH2-CO-CH20H + HOCH2-CHOH-CO-CH2OR

(4) HOCH2-CHOH-CO-CH20H \d HOCH2-CHOH-CHOH-CHO

(5) HOCH2-CHOH-CHOH-CHO __+ HOCH2-CHO + HOCH2-CHO

The first aldol oondensationis unexoeptionable,and the tautcmerizationof

glyoeraldehydeto dihydroxyacetonethrough the common enol is also well

tautomerizesto the aldotetrose. This is simply the aldol oondensation

, and by a simple reverse aldol reaction oan

thus been synthesizedfrom two formaldehydemoleoules.

This mechanism is oertainlyoonsistentwith the operation of small

amounts of glycolaldehyde,glyoeraldehyde,or dihydroqacetone in

process, assuming that a steady state oonoentrationof these intermediates

would be establishedbecause of the competing further condensations.

5 R. Rreslow, J. Amer. Chem. Soo, SO, 3719 (1958).

-thermore, this mechanism explains why benzoylcarbinolcan give both an

immediatereaction and a faster reaction when it is added as catalyst to

the formaldehydereaction mixtures3 for it oan function in place of

glycolaldehyde,thus eliminatingthe induction period, and condensation

reactiona involving benzoylcarbinolmight zell be even faster than those

involving glycolaldehyde,a presumptionwhich is supported by the obeer-

vation that m- and p-cyanobenzoyloarbinol

the p-methoxy compound ia somewhat worae.

e.g. benzoin, could not function in place of glycolaldehydein our