Anchimeric-Assisted Spontaneous Hydrolysis of Cyanohydrins Under Ambient Conditions: Implications for Cyanide-Initiated Selective Transformations

Article abstract of DOI:10.1002/chem.201701497

Nitrile/cyanide hydrolysis is of importance from the perspective of organic chemistry, especially, prebiotic chemistry. Herein we report that cyanohydrins, generated by the reaction of cyanide with β-keto acids and γ-keto-alcohols, spontaneously hydrolyze

Full text of DOI:10.1002/chem.201701497

A Journal of
Accepted Article
Title: Anchimeric-assisted Spontaneous Hydrolysis of Cyanohydrins
Under Ambient Conditions: Implications for Cyanide Initiated
Selective Transformations.
Authors: Jayasudhan Reddy Yerabolu, Charles L Liotta, and
Ramanarayanan Krishnamurthy
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To be cited as: Chem. Eur. J. 10.1002/chem.201701497
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Anchimeric-assisted Spontaneous Hydrolysis of Cyanohydrins
Under Ambient Conditions: Implications for Cyanide Initiated
Selective Transformations.
Jayasudhan Reddy Yerabolu[a,c], Charles L Liotta[b,c]*, Ramanarayanan Krishnamurthy[a,c]
*
Dedication: To Professor Albert Eschenmoser on the occasion of his 92nd Birthday
Abstract: Nitrile/cyanide hydrolysis is of importance from the
perspective of organic chemistry, especially, prebiotic chemistry.
0.1 mol eq.
NaCN
HO
CO2Na
CO2Na
CO2Na
Herein we report that cyanohydrins, generated by the reaction of
cyanide with b-keto acids and g-keto-alcohols, spontaneously
hydrolyze under ambient conditions (aqueous medium, r.t. and a
range of pH). The spontaneous hydrolysis is effected by an
intramolecular-proton transfer and an intramolecular 5-exo-dig attack,
but with a twist. In the case of β-keto acids, the hydrolysis is
mediated by the neighboring carboxylic acid group only at pH values
less than 7, while in the case of g-keto-alcohols the hydrolysis is
mediated by the neighboring hydroxyl group only at pH values
greater than 7. The results, in combination with previous works,
have implications for selective transformations of cyanide-initiated
prebiotic systems chemistry.
a)
+
pH ≥ 13.0
NaO2C
OH
O
2
3
OH
H
C
O
0.5 - 1.0 eq
NaCN
CONH2
OH
CO2Na
HO
1
b)
HO2C
pH < 7.0
4
Scheme 1. The divergent reactions of glyoxylate with cyanide depending on
the pH of the medium.
cyanohydrin of glyoxylic acid, which subsequently underwent a
condensation reaction with unreacted glyoxylic acid. The fact
that the cyano-group (as the cyanohydrin) did not survive, but
was hydrolyzed spontaneously under the mild conditions (near
neutral pH and room temperature) prompted an extended
investigation of this reaction, and of NaCN with a variety of keto-
acids and keto alcohols in water on both the acidic and basic
side of the pH scale. Herein we report on the spontaneous
anchimeric-assisted hydrolysis of cyanohydrins to a-hydroxy
amides under room temperature conditions. In general, we
observe that the ease of cyanide hydrolysis depended on the
specific structure of the cyanohydrin intermediate. Specifically,
the intermediate cyanohydrins were spontaneously hydrolyzed
at room temperature only when (a) the pH of the aqueous
medium was below 7 and a carboxylic acid substituent was
located β to the cyano group or (b) the pH was above 7 and a
hydroxyl substituent was located γ to the cyano group. We
present evidence, primarily based on 13C-NMR and mass
spectral data, that establishes the anchimeric assistance
provided is via an internal proton transfer leading to a 5-exo-dig
attack of the internal nucleophile on the cyano-group. The
results from these studies, combined with those from previous
works, are of interest not only from the perspectives of organic
chemistry[18-20], but also have implications for the selective
transformations/manipulations in the context of prebiotic
systems chemistry[13-15] (such as proto metabolic pathways and
cycles[5,21]).
Introduction
Introduction: The reaction of cyanide to form nitriles and the
subsequent hydrolysis of nitriles to yield amides or carboxylic
acids are classical reactions both in organic synthesis,[1-4] and in
many prebiotic chemistry scenarios[5-8]. Examples include the
Strecker synthesis of amino acids[9,10] and the homologation of
monosaccharides via the Fischer-Kiliani synthesis[11,12]
. In
addition, as of late, the reactions of cyanide have also been
considered in a prebiotic-systems-chemistry perspective.[13-15]
Recently, we reported that reaction of glyoxylate 1 with
catalytic cyanide at pH 13 led to the production tartrate 2 and
oxalate 3 in high yields via a novel deoxalation reaction
(Scheme 1a).[16,17] Within a prebiotic context, however, such a
high pH could be considered problematic. Therefore, in this
study, we began an investigation of a similar set of reactions of
glyoxylate on the acidic side of the pH scale. Surprisingly, the
reaction of glyoxylic acid with 0.5-1.0 equivalent of hydrogen
cyanide at pH
dihydroxysuccinic acid 4 (Scheme 1b) presumably via the
≤
7, produced the 2-carbamoyl-2,3-
[a]
Dr. Jayasudhan R. Yerabolu, Prof. Dr. Ramanarayanan
Krishnamurthy
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Rd, La Jolla, CA 92037, USA
E-mail: rkrishna@scripps.edu
[b]
[c]
Prof. Dr. Charles Liotta
2School of Chemistry and Biochemistry, Georgia Institute of
Technology, Atlanta, GA 30332, USA, E-mail:
charles.liotta@carnegie.gatech.edu
Results and Discussion
NSF-NASA Center for Chemical Evolution, Atlanta, GA 30332
(USA)
Supporting information for this article is given via a link at the end of
the document.
Reaction of cyanide with glyoxylate: The reaction 0.5 eq of
NaCN with glyoxylic acid (1, ≈ 0.5M) at r.t. began with an initial
unadjusted pH of 2 (Scheme 2). Monitoring by 13C-NMR (Figure
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1, bottom spectrum) showed the (fast) formation of glyoxylate-
cyanohydrin 5 adduct along with unreacted glyoxylate as the
major species with the pH slowly rising to 3 over days (Figure
S1-S2). Over time, signals corresponding to both these species
slowly diminished and with concomitant rise in signals attributed
to the (diastereomeric) product 4 (Figure 1, middle spectrum).
The intensity of signals for intermediate 6 was weak (Figure S2),
suggesting that the cyanide moiety in the adduct 6 was
continuously hydrolyzed at r.t. to the amide product (4), thus,
keeping the concentration of 6 low. The reaction proceeds
slowly over days-weeks at r.t. with the pH of the reaction
medium rising to 4.5 and settling around 5 (Figure S3-S5, S8);
complete consumption of starting materials and intermediates
with the clean formation of two diastereomers of the mono-
amide derivative 4 was observed (Figure 1, top spectrum) which
was corroborated by mass spectral analysis (Figure S6-S7).
When one equivalent of NaCN was employed at r.t. (range of pH
≤ 7) the reaction proceeded as above, but relatively faster, to
give the mono-amide 4 along with the cyanohydrin adduct of
glyoxylate
5 (Figure S9). Reactions using doubly labeled
glyoxylate with unlabeled cyanide confirmed the condensation of
two glyoxylate molecules by the increase in the splitting of the
signals in the 13C-spectra (Figure S10) of the 13C-labeled
monoamide derivative 4. Use of labeled Na13CN with unlabeled
glyoxylate showed cleanly the formation of the cyanohydrin-
adduct 5 followed by its disappearance and the concomitant
appearance of the amide signals of 4 in the 13C-NMR spectra
(Figure S11). Again, 13CN-signals of the cyanohydrin group for
the intermediate 6 could not be clearly discerned, suggesting its
continuous consumption in the reaction.
O
ONa
H
C
O
0.5 - 1.0 eq
NaCN
OH
HO
HO
OH
4
HO
ONa
O
3
1
CO2Na
CO2Na
2
5
C
O
C
pH ≤ 7.0
NC
O
NH
1
O
O
N
6
H
(Na)
5
7
O
HO
ONa
OH
OH
H
C
NC
CONH2
OH
CO2Na
HO
NaO2C
O
1
5a
4
0.5 - 1.0 eq
NaCN
HO
ONa
decomposition
NC
pH > 7.0
O
5
Scheme 2. “Glyoxoin reaction” of glyoxylate mediate by cyanide at pH ≤ 7 at room temperature leading to the formation of a carboxamide derivative 4. At pH > 7,
the adduct 5 persists and slowly decomposes by side reactions.
Figure 1. 13C-NMR (H2O with DMSO-d6) monitoring of the reaction of 0.5 equiv. of NaCN with 1 equiv. of glyoxylate at pH < 7 documenting the clean conversion
to the final diastereomeric mixture of amide 4.
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In all these reactions, the pH of the reaction medium was
less than or equal to 7. When the pH of the reaction medium
was maintained higher than 7, the clean formation and/or
hydrolysis of condensation product 6 was not observed. For
example, when a solution of glyoxylic acid whose pH was
adjusted to pH 7 was treated with 0.5 eq. of NaCN, the pH of the
solution raised to pH 12.5 and the cyanohydrin adduct 5 was
formed, but was accompanied by side reactions and a messy
13C-NMR spectrum (Figure S12) indicative of interference from
Cannizzaro[22] type reactions or deoxalation[16] reactions.
2.0 eq NaOH (pH ~ 6.5)
1.0 eq NaCN
a)
pH ~ 12.5
O
O
OH
CN
HO2C
CO2H
NaO2C
CO2Na
+
NaO2C
CO2Na
NaCN
8
8
9
– CO2
b)
1.0 eq NaOH (pH ~ 3.0)
1.0 eq NaCN
pH ~ 8.0
O
O
– CO2
CO2Na
H3C
CH3
H3C
1.0 eq NaCN
pH ~ 6.0
c)
13
10
NaCN
NaCN
NaO2C
HO
HN
OH
OH
OH
CN
9
NaO2C
16
CO2Na
CONH2
CO2Na
CH3
H3C
H3C
O
CN
O
11
14
15
OH
CO2Na
H3C
CONH2
12
Scheme 3. Reaction of 1,3-acetone dicarboxylic acid (8, 0.68 M) with 1.0 equivalent of sodium cyanide (a), (b) at pH greater than 7, and (c) at pH ≤ 7; all at room
temperature.
Figure 2. Progress of the reaction of NaCN with 1,3-acetone dicarboxylic acid 8 as documented by 13C-NMR spectra (H2O with drops of D2O), giving rise to citric
acid amide derivative 16.
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a)
HO
H3C
HN
OH
OH
CN
O
O
O
1.0 eq NaCN
CO2Na
CONH2
CO2Na
H3C
H3C
H3C
OLi
pH ≤ 7
O
10
12
11
18
b)
O
OH
OH 1.0 eq NaCN
pH < 7
H3C
No further reaction
CO2Na
H3C
O
CN
17
19
Scheme 4. (a) Reaction of acetoacetic acid (10, 0.23 M) with 1.0 equivalent of NaCN at pH ≈ 4.5; (b) Reaction of pyruvic acid (17, 0.45 M) with 1 equivalent of
NaCN at pH 3.0; all at room temperature.
In another experiment, the glyoxylate-cyanohydrin adduct 5 was
separately formed at pH 6.5, and the pH was adjusted to pH ≈
10.5 (Figure S13). The consumption of 5 was observed through
side reactions again with no clear indication of formation
condensation product 6 or its hydrolysis product 4.
decarboxylate to afford acetoacetic acid 10 and acetone 13, and
their respective cyanohydrin adducts 11 and 14 (Scheme 3a).
When one equiv. of NaOH was used (pH ≈ 3) followed by
addition of NaCN, the pH rose to 7.5–8 within days and with
similar results as with 2 equiv. NaOH (Scheme 3b). However,
13C-NMR indicated minor peaks that could be attributed to (trace
amounts) of a citric acid-like derivative (Figure S15). This
prompted addition of 1 equiv. of NaCN directly to 8 (pH
unadjusted ≈ 2.5) even though it meant the risk of higher rates of
This cyanide-mediated “glyoxoin”[16] (in analogy to the
formoin) type condensation of glyoxylate at pH ≤ 7, resulting in
the formation of a carboxamide derivative 4 was unexpected
(based on literature precedence) for two reasons: (1) a high pH
was thought to be necessary[16] for deprotonating the a-proton of
the glyoxylate-cyanohydrin adduct 5 and (2) generally, highly
acidic or basic pH[23] combined with elevated temperatures[24-26]
is needed to hydrolyze the cyano-group (such as in 6) to give
the corresponding amide derivative 4. The ease of the hydrolysis
of cyano-group of 6 at room temperature led us to hypothesize
that an internal anchimeric carboxylate/acid assistance[27] via a
5-membered ring intermediate 7 (Scheme 2) may have been
responsible. Such an intramolecular hydrolysis is reminiscent of
the borate-buffer mediated hydrolysis of cyanohydrins[28,29] and
aldehyde mediated hydrolysis of a-aminonitriles[30,31] at high-pH
(pH ≥ 10). However, our results indicate that the pH of the
medium could also be on the lesser side of neutrality. To test
this hypothesis, and the generality of this anchimeric assistance,
we expanded the scope of the substrates to other keto-acids
which are of relevance to the chemistries in the context of
decarboxylation of
8 at the acidic pH. Nevertheless, the
formation of a citric acid derivative in 13C-NMR was observed
within hours with the pH rising to pH 5–6, with negligible side
reactions due to competing decarboxylations (Figure S16-S17).
Within 3 days, the peaks attributable to a citric acid derivative
(surmised to be the amide derivative 16, (Scheme 3c, Figure
S18-S19) was dominant, along with small amounts of 10, 12 and
13 as side products formed from decarboxylation of 8 (Figure 2).
Spiking with citric acid, and mass-spectral data confirmed that it
was indeed the amide derivative 16 (Figure S20-S22). The
spontaneous hydrolysis of the cyanide moiety in cyanohydrin
derivative 9 parallels the observation made in the glyoxylate
reaction (Scheme 2); also, the hydrolysis to the corresponding
a-hydroxy amide was observed only when the pH was less than
or equal to 7 and not when above 7. The rate of cyanohydrin
formation 9, however, was much slower (days) when compared
to the formation of cyanohydrin 5 (30 min.) attesting to the
reactivity of the glyoxylate carbonyl group versus the keto-group
of 8.
prebiotic chemistry[15,32] and proto-metabolic pathways[5,21]
.
Reaction of cyanide with 1,3-acetone-dicarboxylic acid
(Scheme 3): 1,3-acetone-dicarboxylic acid 8 was chosen for two
reasons: (1) the two-carboxylic acid groups have the same b-
keto-relationship as in the intermediate 6 in Scheme 2 and (2)
the hydrolysis product is expected to lead to citric acid, an
important biological compound in the tricarboxylic acid (TCA)
cycle[5]. Also, such a reaction may be relevant to the types of
reaction products found in the meteorites[33] and proto-metabolic
Reaction of cyanide with acetoacetic acid and pyruvate: Based
on the above results, acetoacetic acid 10, also a b-keto
carboxylic acid but with only one carboxylate moiety, was
reacted with cyanide at pH 3, 7 and 13 (Scheme 4a). While the
cyanide addition was found to occur (slower relative to pathways
starting from 1 or 8) at pH = 3-4.5 (Figure S 23) and 7-7.5
(Figure S25), no cyanohydrin-adduct 11 formation was observed
reactions[34,35]
.
Since 8, a b-keto carboxylic acid, is prone to decarboxylation, at pH 13 by 13C-NMR (S26). Paralleling the outcomes observed
we reasoned that as the dicarboxylate it may be more stable and
available to react with NaCN. Therefore, two equiv. of aq. NaOH
was added to make the disodium salt of 8 (pH ≈ 6.5) followed by
one equiv. of NaCN. Within 10 min. the pH increased to 12.5
and 13C-NMR indicated the formation of the cyanohydrin adduct
9. The reaction however, over days, stalled at the cyanohydrin
adduct with no anchimeric assisted hydrolysis of the cyanide
(Figure S14). Rather, the unreacted portion of 8 began to
for 1,3-acetone-dicarboxylic acid (Scheme 3), spontaneous
hydrolysis of cyanohydrin-adduct 11 occurred at pH 3-4.5 to
form the corresponding succinamide derivative 12 (Figure S23-
S24); however, the reaction at pH 7 (or higher) did not proceed
beyond the cyanohydrin adduct 11. Reaction with pyruvate 17
(at pH 3) resulted in the faster (within 30 min) and complete
formation of the corresponding cyanohydrin adduct 19 (Scheme
4b), but with no further reaction (Figure S27).
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OH
O
(leading to a five-membered cyclic intermediate) indeed is
necessary for the hydrolysis of the cyanohydrin adduct.
OH
O
NC
O
1.0 eq NaCN
The observations with the carboxylic acids led to the
question of whether a neighboring hydroxyl group (with similar
1,5-positional relationship to the cyano group) would also show
the same behavior and be capable of spontaneous
intramolecular transformation of the cyanohydrins to the
corresponding a-hydroxy amides. This is akin to the Kiliani-
reaction of cyanides with aldoses, where cyclic 5-membered ring
participation of a hydroxyl-group is invoked for hydrolysis of the
cyanohydrin to give the corresponding lactones under acid/base
treatments.[12,41,42]
No further
reaction
O
OH
pH < 7
O
OH
ONa
21
20
4
HO
5
3
NaO
2
1
HO
6
C
O
O
N
6-exo-dig
Reaction of cyanide with 1,5-dihydroxy pent-3-one: NaCN
was reacted with 1,5-dihydroxy pent-3-one 22. This substrate is
analogous to acetone-1,3-dicarboxylic acid, where both the
carboxylic acid moieties have been reduced to corresponding
alcohols (Scheme 6a). When subjected to the identical acidic
reaction conditions (pH < 7) as above, only the formation of the
cyanohydrin adduct 23 was observed, with no further hydrolysis
of 23 even after 5 days at rt (Figure S29). However, when the
reaction was conducted starting at pH 7.5, we observed the
hydrolysis of the cyanohydrin adduct giving rise to the
corresponding amide 25 in 12 h at rt (pH changing to ≈ 8), which
continued to proceed over a period of 5 days (pH ≈ 8.5, Figure
S30). The formation of carboxamide 25 was also confirmed by
mass spectral data (Figure S31). This result indicated that (a)
there is indeed a difference in the pH requirements for the
anchimeric assistance of carboxylic acid versus hydroxyl group
in these acyclic systems – the former requiring a pH below 7
while the latter a pH above 7, and (b) there is no need to have a
highly basic pH (like in the classic Kiliani-Fischer protocols)
when there is anchimeric assistance from the hydroxyl group
with a 1,5-relationship.[12,41,42]
To test whether the 1,5-positional relationship (5-exo-dig) also
holds good for a nieghboring hydroxyl group, the reaction of 4-
hydroxybutan-2-one 26 and 5-hydroxypentan-2-one 30 were
investigated with NaCN (Scheme 6b and 6c). Under acidic pH,
as observed for 22, both compounds formed the cyanohydrin
adducts 27 and 31 respectively, but no hydrolysis of these
adducts were observed even after 3-5 days (Figure S32). On the
other hand, when the reactions were repeated at pH 7.5-8.0,
cyanohydrin adduct 27, which has a 1,5-relationship, was not
only found to hydrolyze to the corresponding a-hydroxy amide
29 (2 days, Figure 3) but further converted cleanly to the
corresponding a-hydroxy acid (Figure S33-S35), which is
consistent with anchimeric assisted hydrolysis of the amide as
reported by Kirby.[43] However, cyanohydrin adduct 31, which
has a 1,6-relationship, was found to persist (Figure 4) over days
with no further hydrolysis (Figure S36, S37); at pH 13, the
formation of the cyanohydrin adduct itself was not observed
(Figure S38). Observations from the above reactions confirm
that (1) there is a pH divergence of the intramolecular reactivity
of carboxylic acid (pH < 7) versus hydroxyl group (pH > 7) and
(2) a 1,5-positional relationship of the attacking nucleophile to
the cyano-group is required for both the carboxylic acid and
hydroxyl groups; that is, a 5-exo-dig (as opposed to a 6-exo-dig)
cyclic intermediate is preferred.
Scheme 5. (a) Reaction of 4-oxoheptanedioic acid (20, 0.28 M) with 1.0
equivalent NaCN at pH 4-5.5 at room temperature.
The resistance to hydrolysis of the pyruvate-cyanohydrin-adduct
19 indicates that neither the intramolecular attack of the
carboxylic acid oxygen (via a four-membered ring intermediate),
nor an intermolecular attack of a water molecule on the cyano-
group of 19, is taking place. The above set of reactions support
a 5-exo-dig attack of the internal carboxylate nucleophile on the
cyanide, via a five-membered ring intermediate. This would
necessitate a 1,5-positional relationship between the cyano-
group (of the cyanohydrin) and the attacking oxygen-moiety of
the carboxylic acid. It immediately raises a question as to
whether a 1,6-positional relationship leading to a six-membered
ring intermediate (via
a 6-exo-dig attack of the internal
nucleophile) would be possible, since such 6-exo-dig additions
on a cyano moiety are known.[36-38]
Reaction of cyanide with 4-oxoheptanedioic acid: To answer
the question whether a 1,6-relationship between the carboxyl
and the cyano-group would lead to hydrolysis, NaCN was
reacted with 4-oxoheptanedioic acid 20, a substrate in which the
carboxylates are gamma in relation to the keto group (Scheme
5). This will result in a 1,6-relationship in 21, necessitating a six-
member(6-exo-dig) anchimeric-assisted intermediate. Though
cyanohydrin adduct 21 formation was observed (pH ≈ 5), no
hydrolysis of 21 was observed under the identical conditions
where cyanohydrin adduct 15 of 1,3-acetone dicarboxylic acid 8
was spontaneously hydrolyzed. Further heating (50°C) did not
change this result. This observation that the cyano-group of 21
is resistant to hydrolysis (under these conditions) demonstrates
that a 6-exo-dig participation of the carboxylate group is not
taking place (Figure S28). While 6-exo-dig cyclization on a
cyanide moiety are not forbidden and are known,[27,36-39] there
are also examples where there is a clear preference for the 5-
exo-dig.[12] The stability of the resulting exo-double bond five-
membered ring (5-exo-dig) versus the instability of the exo-
double bond six-membered ring (6-exo-dig) has been proposed
to play a role in this preference.[40] The results, while consistent
with the latter observations and interpretations[12,40], imply that
further activation of the cyanide is necessary[36-38] for the 6-exo-
dig attack to take place and, unlike the 5-exo-dig, is not
‘spontaneous’. This strengthens the supposition that a 1,5-
positional relationship between the carboxylate and the nitrile
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pH ≤ 7
a)
No further reaction
OH
O
2
1.0 eq NaCN
4
5
HO
23
OH
1
HO
OH
3
OH
C
OH
HO
22
N
HO
OH
pH 7.5 - 8.0
CONH2
HN
O
25
+ the acid
24
b)
OH
OH
CN
O
O
OH
1.0 eq NaCN
H3C
HN
H3C
OH
27
H3C
OH
H3C
29
OH
pH 7.5 - 8.0
CONH2
26
O
28
c)
OH
3
1.0 eq NaCN
5
pH 7.5 - 8.0
OH
2
No further reaction
H3C
H3C
4
30
C
6
OH
1
N
31
Scheme 6. Reaction of NaCN with g-hydroxy ketones 22, 26, and d-hydroxy ketone 30 illustrating the 1,5-positional relationship and the pH > 7 requirements for
intramolecular hydrolysis.
Figure 3. 13C-NMR spectra (H2O with DMSO-d6) of the reaction of NaCN with 4-hydroxybutan-2-one 26 showing clean conversion to the hydrolyzed products
amide and the corresponding acid.
With these conclusions in hand we probed the predictions
from the reaction mechanism by expanding to other substrates
These substrates were also chosen due to their potential role in
the context of the glyoxylate scenario[21], and are generated by
the reactions involving glyoxylic acid 1.[32] If the above
observations have predictive value, then the cyanohydrin adduct
from these substrates (33, 36 and 39, Scheme 7) are expected
to hydrolyze only when pH is greater than 7 and not when pH is
less than 7, since it is only the hydroxyl-group that has the
correct 1,5-positional relation to the cyano-group.
within the context of prebiotic systems chemistry[14]
. We
designed three a-keto carboxylic acid substrates 2-hydroxy-4-
ketoglutarate 32[44], 35 and 38[45] (Scheme 7) which contain both
a hydroxyl (with a 1,4-relationship to the keto group, leading to a
5-exo-dig attack) and
a carboxylate group (with a 1,5-
relationship to the keto group, leading to a 6-exo-dig cyclization).
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Figure 4. 13C-NMR spectra (H2O with DMSO-d6) of the reaction of NaCN with 5-hydroxypentan-2-one 30 documenting the cyanohydrin formation with no further
progress (hydrolysis to the corresponding amide).
33b
OH
3'
5'
4'
NaO2C
OH
O
6-exo-dig
2'
O
6'
C
1'
N
H
a)
pH ≤ 7
No further reaction
OH OH
OH OH
O
OH
1.0 eq NaCN
O
HO
O
NaO2C
C
ONa
33
O
OH
N
32
NaO2C
CO2Na
CONH2
pH > 7
34
OH
2
4
5-exo-dig
ONa
3
NaO2C
5
1
O
C
O
H
N
33a
b)
pH ≤ 7
No further reaction
OH CO2Na
OH CO2Na
O
OH
O
2
4
3
1.0 eq NaCN
CO2Na
HO
NaO2C
OH
5
C
1
OH
O
HO
35
O
N
36
CO2Na
OH
37
NaO2C
H2NOC
pH > 7
c)
OH OH
1
OH OH
O
OH
HO
H2NOC
1.0 eq NaCN
pH > 7
4
HO
3
O
CO2Na
2
CO2Na
5
C
OH
40
OH
HO
OH OH
38
N
39
Scheme 7. Reaction of NaCN with keto-substrates that contain both the hydroxyl group (with a 1,5-positional relationship) and the carboxylate group (with a 1,6-
positional relationship) demonstrating the requirement of a 1,5-relationship for enabling the spontaneous hydrolysis of the cyano-group.
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Figure 5. 13C-NMR spectra (H2O with DMSO-d6) of the reaction of NaCN with (middle spectra) citroylformate 35, documenting (top spectra) the cyanohydrin
formation with no further progress at pH < 7 and (bottom spectra) the addition-followed-by-hydrolysis product at pH > 7.
A
B
O
4
H
O
H
3
1
O
2
3
1
4
4
5
N
O3
O3
2
H
H
N
C
6
C
HO
HO
5
H
5
O
5
H
4
H
2
2
1
1
H
pH > 7
pH < 7
pH < 7
O
O
O
O
H
N
H
O
H
O
C
O–
H
H
H
O
H
O
C
N
C
N
H
HO
HO
The internal proton source activates the
nitrile via the participation of a water
molecule
water is not acidic enough to
protonate the nitrile N atom for
activation
The internal proton source not ideally
placed for intramolecular activation
pH < 7
Water O is not basic enough to
deprotonate the alcohol H atom
pH > 7
pH > 7
H
H
H
N
H
O
H
H
O
C
O
O
H
O
H
N
H
O
H
C
C
N
HO
HO
HO
H
H
O
H
N
water O is basic enough to
deprotonate the H atom on the O
atom of the alcohol attacking the
nitrile
O
H
C
The internal proton source not ideally
placed for intramolecular activation
Hydroxyl O is not nucleophilic
enough to attack the nitrile C atom
Scheme 8. Rationalization of the pH dependence of the anchimeric assistance provided by the carboxylic acid group (pH < 7) and the alcoholic hydroxyl group
(pH > 7), referring to (A) 5-exo-dig that does take place, and (B) 6-exo-dig attack that does not take place.
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pH greater than 7 and not below – suggests that there are two
factors critical for the spontaneous hydrolysis of the
cyanohydrin: (1) the proper positioning of the nucleophile for a 5-
exo-dig attack, (2) and, more importantly, an intramolecular
proton mediated activation of the nitrile from the internal
carboxylic acid or the alcoholic-hydroxyl group, perhaps through
the participation of a water molecule (Scheme 8A). This implies
that just as the intramolecular nucleophilic attack is important, so
is the activation of the cyano-group mediated by intramolecular
(water-hydrogen bond mediated) proton transfer[46]. Involving a
water molecule to mediate the internal-proton-transfer-activation
results in a 5-membered transition state which may be more
energetically favorable than a direct internal-proton-transfer-
activation (a 4-membered transition state). This would involve
two 5-membered rings (one for the nucleophilic attack and one
for the proton transfer) as depicted in Scheme 8A. This postulate
also suggests another plausible reason for the failure of
cyanohydrins such as 21 (Scheme 5) and 31 (Scheme 6c) to
react further. Apart from the previously pointed out 6-exo-dig
requirement leading to an unfavorable exo-double bond on a
developing six-membered ring transition state[40], the geometrical
requirement for an internal proton activation may also not be that
favorable; here, a 6-membered ring (6-exo-dig) required for the
nucleophilic attack may distort the 5-membered ring geometry
required for the internal proton transfer (Scheme 8B). And,
without the internal-proton-transfer-activation of the cyano-group
in 21 and 31, the hydrolysis mediated by intramolecular attack of
the oxygen nucleophile is not expected to happen. This line of
argument seems to be in consonance with the literature data
showing the necessity of metals[36-38] for activating the cyano-
group to enable intramolecular 6-exo-dig nucleophilic attacks.
We are currently pursuing computational studies (ab initio
OH
CO2Et
CONH2
H3C
43
OH
O
O
O
1.0 eq NaCN
CO2Et
H3C
H3C
OEt
OEt
pH ≤ 7
CN
41
42
OH
1.0 eq NaCN
pH > 7
H3C
OEt
45
H3C
CN
44
OH
H3C
OEt
CONH2
46
Scheme 9. Reaction of the ethyl acetotacetate 41 and 4-ethoxybutan-2-one
44 with NaCN forms only the corresponding cyanohydrin adduct with no
further hydrolysis to the respective amides
Accordingly, two sets of reactions of 32 and 35 with NaCN,
one at pH 3-4 and one at pH 7-8 and another at pH 13.0 were
carried out (Scheme 7). With 38, reactions only at pH > 7 were
carried out, since at pH < 7 (pH ≈ 3) 38 was found to be unstable.
In these cases, as predicted, hydrolysis of the cyanohydrin-
adduct to the corresponding amides 34, 37 and 40 was
observed only when the pH was greater than 7 (Figure S39-S57). calculations) that would be able to shed more details of the
proposed mechanism in Scheme 8.
For example, in the case of hydroxy-acid 35, the cyanohydrin-
adduct 37 was formed under both the acidic and basic
conditions, but hydrolysis to the amide was observed only when
pH was greater than 7 (Figure 5); and, furthermore, even the
corresponding acids were also observed (Figure S48-S50). This
indicated that only the hydroxyl group which has a 1,5-positional
relationship to the cyano-moiety of 33, 36 and 39 participated in
the intramolecular 5-exo-dig mediated hydrolysis leading to the
corresponding amides (and even to the acids in certain cases).
The carboxylate moiety, which has a 1,6-relationship, did not
participate in this reaction. We wanted to check the ‘reverse’-
substrates with both a hydroxyl (with a 1,5-relationship to the
keto group, leading to a 6-exo-dig attack) and a carboxylate
group (with a 1,4-relationship to the keto group, leading to a 5-
exo-dig cyclization). Here, the hydrolysis of the cyanide would
be expected to occur only at pH ≤ 7 mediated by the carboxylic
acid group, with the hydroxyl group not participating.
Unfortunately, the substrates we considered proved unstable,
and, therefore, we were unable to check the reverse-possibility.
Mechanism: The consistent effect of pH on determining
which group provides the intramolecular anchimeric assistance –
the carboxylic acid group aiding the hydrolysis of the cyano-
group only at pH lower than 7 and not above, while the
alcoholic-hydroxyl group hydrolyzing the cyano-group only at a
That an internal proton source[46] is necessary to enable the
spontaneous hydrolysis of cyano-group was tested with two
substrates, ethyl acetoacetate 41, and ethyl ether of butan-2-one
44, where the protons have been replaced by ethyl groups, thus
eliminating the internal proton source (Scheme 9). These two
substrates should add the cyanide to form the corresponding
cyanohydrin derivatives 42 and 45 respectively; but then there
should be no further conversion (no spontaneous hydrolysis)
even under the most favorable conditions (pH < 7 for 42 and pH
> 7 for 45)) to the corresponding amides 43 and 46, if the
internal proton source is necessary. And this is indeed what is
observed by 13C-NMR spectroscopy (Figures S58 and S59).
Under the conditions where the cyanohydrin adducts 11 and 27
(which have the internal proton source) are found to hydrolyze
spontaneously to afford the corresponding amides 12 and 29 in
5 days at room temperature, cyanohydrins 42 and 45 (which do
not have the internal proton source) are stable as such (even
after 15 days at r.t.), and do not form the corresponding amides
43 and 46 (Figure S58-S59). This observation supports the idea
that the internal proton is necessary for the activation of the
cyano-group, enabling the subsequent intramolecular oxygen
nucleophilic attack for its conversion to the corresponding amide
(and acid).
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10.1002/chem.201701497
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Implications in the context of prebiotic systems chemistry:
Prebiotic systems chemistry has come to the forefront in recent
years [14,47] and cyanide initiated reactions play a major role as
exemplified by the work of Sutherland[13,15] and Powner[49]. In
that context, the results presented here provide for selective
transformations which would be important in prebiotic chemistry
where generally mixtures of reactants and products co-exist.[33]
Experimental Section
Description of materials and experimental methods, NMR spectra, mass
spectrometry data of isolated compounds, experimental comparison
NMR spectra, quantitative NMR information, calculated yields, and
chemical shift information are provided in the supporting information.
Acknowledgements
O
OH
OH
OH
H3C
NC
19
H3C
17
This work was jointly supported by NSF and the NASA
Astrobiology Program under the NSF Center for Chemical
Evolution, CHE-1504217. We thank Professor Ryan Shenvi for
comments and feedback on the manuscript.
O
O
NaCN initiated addition
followed by hydrolysis
OH
O
HO2C
CO2H
HO2C
CO2H
CONH2
CN
12
8
Keywords: Anchimeric Assistance • Spontaneous Hydrolysis of
Cyanohydrins/Nitriles • a-Hydroxy Amides • Prebiotic Systems
Chemistry
HO2C
CO2H
HO2C
CO2H
48
47
O
OH
Scheme 10. Potential selective transformation of only the 1,3-acetone
dicarboxylic acid 8 in the presence of pyruvic acid and a-ketoglutaric acid (a
structural isomer of 8).
[1]
[2]
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cyanide would be able to mediate selective transformations of
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5-exo-dig
Selection by Hydrolysis. Cyanide
initiated addition followed by
hydrolysis could be useful tool to
select among a set of substrates.
Jayasudhan Reddy Yerabolu1,3, Charles
L Liotta2,3*, Ramanarayanan
pH > 7
H2NOC
pH ≤ 7
N
C
N
C
OH
H2NOC
OH
OH
OH
Krishnamurthy1,3
*
HO
HO
R
O
R
HO
N
O
O
HO
R
R
pH ≤ 7
pH > 7
Page No. – Page No.
N
C
HO
OH
Anchimeric-assisted Spontaneous
Hydrolysis of Cyanohydrins Under
Ambient Conditions: Implications for
Cyanide Initiated Selective
C
No
No
hydrolysis
hydrolysis
HO
pH ≤ 7
HO
pH > 7
R
R
6-exo-dig
Transformations.
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