Methylene group transfer in carbonyl compounds discovered in silico and detected experimentally

Article abstract of DOI:10.1002/cphc.201800945

A previously unknown transformation of aldehydes, ketones, and carboxylic acid derivatives leads to the formation of substituted oxiranes, aziridines, and azirines as shown by DFT and MP2 computations. Formations of 2,2-dimethyloxirane-d₈ from acetone-d₆, phenylazirine-d₂ from benzonitrile and 2- methyl-2-(4-hydroxyphenyl)-oxirane from 4-hydroxyacetophenone were detected experimentally by electrospray ionization mass-spectrometry with a heated desolvating capillary. This reaction is a truly concerted process characterized by high activation barriers (activation enthalpies 320-480 kJmol_-1).

Full text of DOI:10.1002/cphc.201800945

Accepted Article
Title: Methylene Group Transfer in Carbonyl Compounds Discovered in
Silico and Detected Experimentally
Authors: Ilya Gridnev, Alexander Zherebker, Yuri Kostyukevich, and
Eugene Nikolaev
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10.1002/cphc.201800945
ChemPhysChem
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Methylene Group Transfer in Carbonyl Compounds
Discovered in Silico and Detected Experimentally**
Ilya D. Gridnev*[a], Alexander Zherebker[b], Yury Kostyukevichb] and Eugene Nikolaev[b]
Abstract: Previously unknown transformation of aldehydes, ketones
and carboxylic acid derivatives leads to the formation of substituted
oxiranes, aziridines and azirines as shown by DFT and MP2
computations. Formations of 2,2-dimethyloxirane-d8 from acetone-d6,
phenylazirine-d2 from benzonitrile and 2-methyl-2-(4-hydroxyphenyl)-
oxirane from 4-hydroxyacetophenone were detected experimentally
by electrospray ionization mass-spectrometry with heated desolvating
capillary. This reaction is a truly concerted process characterized by
high activation barriers (activation enthalpies 320-480 kJ/mol).
Transformation of carbonyl compounds and derivatives of
carboxylic acids builds a nucleus of contemporary organic chemistry.
There are numerous known reactions employing carbonyl
compounds resulting in deep and variegated structural changes
affording synthesis of useful products or intermediates.[1-5]
Here we report a so far unpublished reaction, non-catalytic
scrambling of a methylene moiety of the carbonyl compounds and/or
derivatives of carboxylic acids located in silico and experimentally
detected by ultrahigh resolution mass spectrometry with
electrospray ionization.
While scanning the approach of the methyl group of one acetone
Figure 1. Transition states for formation of 2,2,-dimethyloxirane and
molecule to the carbonyl group of the other molecule of acetone, we
have observed a characteristic maximum whose geometry was later
used for the location of the corresponding transition state TS1
(Scheme 1, Figure 1).
acetaldehyde from two acetone molecules computed by two different theoretical
approaches. Similar structures (interatomic distances in Å are shown) and
thermodynamic parameters (enthalpies in kJ mol-1, entropies in J mol-1 K-1 are
shown) were computed. Blue arrows show displacement vectors in the TS.
IRC Analysis confirmed formation of acetaldehyde 2 and 2,2-
dimethyloxirane 3 from two molecules of acetone 1 as a truly
concerted process characterized by multidirectional movement of
hydrogen atom and CH2 group (Figure 1).
This discovery prompted us to search experimental evidence of
the occurrence of this transformation under experimental conditions.
Taking into account the high activation barrier and significantly
endothermic character of oxirane formation (Table 1), we attempted
to verify the computational results experimentally via mass-
spectrometric analysis of acetone-d6 solution passing through heated
desolvating capillary of electrospray (ESI) ionization source.[6]
This new method proved its versatility for detecting reactive
intermediates and products in reactions with high activation
barriers.[6] Moreover, via coupling a heated desolvating capillary
with ESI, reaction rates of some reactions can be increased for up to
five orders of magnitude, thus making feasible a wide range of
synthetic reactions not possible in a single phase.[7] This is achieved
via creating interface with huge surface-to bulk ratio.[8] A series of
the most recent studies proved reliability and fruitfulness of this
method.[9] In our experiments we have used deuterated substrates for
further increasing the sensitivity.
Scheme 1. Computed reaction of two acetone molecules yielding acetaldehyde
and 2,2-dimethyloxirane.
[a]
[b]
Prof. Dr. Ilya D. Gridnev
Graduate School of Science
Tohoku University
Aramaki Aza Aoba 6-3, Aoba-ku, Sendai, 9808578, Japan
E-mail: igridnev@m.tohoku.ac.jp
Dr. Alexander Zherebker, Dr. Yury Kostyukevich. Prof Dr Eugene
Nikolaev
Scheme 2 summarizes the results of two independent
experiments that reliably and reproducibly demonstrated formation
of 2,2-dimethyloxirane-d8 in the temperature interval 200-300 oC.
Center of Life Science
Skolkovo institute of Science and technology
3 Nobelya str., Moscow, 121205, Russia
E-mail: a.zherebker@skoltech.ru, e.nikolaev@skoltech.ru
**
Supporting information for this article is given via a link at the end of
the document
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Table 1. Scope of the Intermolecular CH2 group transfer.a,b
Starting compounds
Products
TS
TS1
 cm-1
531i
H≠,
kJ mol-1
393
H,
kJ mol-1
134
S≠,
J mol-1 K-1
-50
S,
J mol-1 K-1
-37
TS2
TS3
TS4
TS5
756i
645i
402
406
423
456
134
130
146
151
-67
-96
-63
-46
-33
-29
-46
-33
804i
1072i
TS6
TS7
TS8
730i
520i
389
359
464
146
113
184
-63
-63
-46
-50
-25
-13
1030i
TS9
TS10
TS11
TS12
1004i
626i
445i
190i
473
431
351
347
192
197
197
151
-63
-29
-75
-29
-50
-25
-42
-25
TS13
TS14
625i
820i
427
444
117
197
-54
-59
-29
-42
TS15
TS16
745 i
849 i
498
494
201
178
-54
-1
-67
13
aB97XD/6-31G(d,p)/SMD; bTS1-TS13 in acetone, TS14-TS16 in acetonitrile.
Inspired by these results we further studied the scope of this new
transformation computationally and experimentally.
was computed for the reactions having CF3 group as a CH2 acceptor
(TS7) or dimethylacetamide as a CH2 group donor (TS11 and TS12).
The activation barriers computed for the reaction of nitriles with
acetone were the highest among the studied reactions. This did not
prevent experimental detection of the corresponding azirine formed
in the reaction with benzonitrile, although it was necessary to apply
a higher temperature (Scheme 3).
Computational screening of various combinations of the starting
carbonyl compounds showed that this transformation has a general
character (Table 1). Imine as well as derivatives of carboxylic acids:
esters, fluoroanhydrides, amides, and nitriles also gave in silico the
corresponding products. Notable decrease of the activation barrier
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Scheme 2. Experimental detection of protonated 2,2-dimethyloxirane-d6 4.
Results of two independent experiments are shown. Second reaction product,
acetaldehyde-d4 was not observed, since its molecular weight is beyond the
detection range. Measured HRMS data of protonated acetone 5 are shown for
reference.
Scheme 5. Experimental detection of CH2 group transfer from 4-
hydroxyacetophenone 7 to acetone-d6 1 at 300 oC. Formation of 4 and 8 is also
observed due to the self-reaction of acetone-d6 (Scheme 2) and CD2 group
transfer from 1 to 7 (Scheme 4). Second reaction product, acetaldehyde-d4, of
the self-reaction of acetone-d6 was not observed, since its molecular weight is
beyond the detection range. Computed imaginary frequencies (cm-1), activation
and reaction enthalpies (kJ mol-1), activation and reaction entropies (J mol-1 K-
1) (B97XD/6-31G(d,p)/SMD(acetone).
Interestingly, computations of the alternative pathway in the
reaction of acetone 1 with acetonitrile provided trisubstituted
oxirane 11 and dihydrogen (Scheme 6, Figure 2a) instead of
expected 3 and HCN.
Scheme 3. Experimental detection of deuterated azirine formation from
benzonitrile and acetone-d6. Formation of 4 is also observed due to the self-
reaction of acetone-d6 (Scheme 2). Second reaction product of both reactions,
acetaldehyde-d4, was not observed, since its molecular weight is beyond the
detection range.
This transformation together with an intramolecular reaction leading
to the formation of the corresponding oxirane 6 and degenerate CH2
group transfer in 7 (Scheme 7, Figure 2b) outlines the wide scope of
the new reaction.
Scheme 6. Computed reaction of acetone with acetonitrile (B97XD/6-
31G(d,p)/SMD(acetonitrile). Computed imaginary frequency (cm-1), activation
and reaction enthalpies (kJ mol-1), activation and reaction entropies
(J mol-1 K-1).
Scheme 4. Experimental detection CD2 group transfer from acetone-d6 to 4-
hydroxyacetophenone 7 at 200 oC. Formation of 4 is also observed due to the
self-reaction of acetone-d6 (Scheme 2). Second reaction product of both
reactions, acetaldehyde-d4, was not observed, since its molecular weight is
beyond the detection range. Computed imaginary frequencies (cm-1), activation
and reaction enthalpies (kJ mol-1), activation and reaction entropies (J mol-1 K-
1) (B97XD/6-31G(d,p)/SMD(acetone).
When either of different starting compounds can be a CH2 group
donor, two different reactions can take place (Scheme 4, 5). At 200
oC only the product of CD2 group transfer from acetone-d6 via TS17
was observed (together with 4, Scheme 4), whereas at the
temperatures approaching 300 oC both reactions took place
simultaneously (Scheme 5). Noteworthy, another product of the CH2
a
b
Figure 2. Computed transition states for formation of oxirane 11 (left,
B97XD/6-31G(d,p)/SMD(acetonitrile)) and degenerate rearrangement in 14
(right, B97XD/6-31G(d,p)/SMD(heptane)).
group
transfer
from
4-hydroxyacetophenone,
4-
hydroxybenzaldehyde was also observed.
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In conclusion, we have located computationally and detected
Acknowledgements
experimentally
a previously unknown reaction of carbonyl
compounds – pericyclic transfer of a CH2 unit from one carbonyl
group to another. Although the activation barriers are high, they
might decrease by appropriate choice of a catalyst and accurate
tuning of the conditions of microdroplets generation,[10] giving
access to practically important transformations. These findings
demonstrate potential of thorough computational studies of simple
molecules and versatility of heated capillary electrospray mass
spectrometry experimental detection of thermodynamically unstable
products in the reactions with high activation barriers.
IDG thanks Prof. Masahiro Terada (Tohoku University) and Prof.
Wanbin Zhang (Shanghai Jiao Tong University) for their
continuous support and fruitful discussions.
AZ and YK
acknowledge financial support from Russian Science Foundation
through Grant No. 18-79-10127.
Keywords: carbonyl compounds • ab initio calculations • MS
spectrometry • heated capillary • DFT
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Scheme 7. Computed intramolecular formation of oxirane 13 and degenerate
rearrangement in 14 (B97XD/6-31G(d,p)/SMD(heptane)). Computed
imaginary frequencies (cm-1), activation and reaction enthalpies (kJ mol-1),
activation and reaction entropies (J mol-1 K-1).
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Experimental Section
DFT Computations were carried out using the long-range corrected hybrid
functional with damped atom—atom dispersion (B97XD)11 as implemented in
the GAUSSIAN 09 software package12 on the 6-31G(d,p) basis. MP2
computations applied the same basis. Solvent effects were accounted by
carrying out optimizations in the SMD force field13 (acetone, acetonitrile or
heptane).
All chemicals were of reagent grade or higher. Methanol (Lab-Scan, HPLC
grade) was used as a solvent for MS experiments. For measuring mass spectra
a custom built QExactive Orbitrap mass spectrometer (Thermo) equipped with
ion funnel and extended metal desolvating capillary and electrospray ionization
source was used.[14] Mass spectra were recorded by Orbitrap in positive ion
mode with the resolving power of 140 000. Heating of capillary was performed
using lab power supply OJE QJ3003C III implemented in series mode. Mass-
spectra treatment and modelling were performed with Thermo Xcalibur 3.0
software.
14 Y. Kostyukevich, E. Nikolaev, Analytical chemistry 2018, 90, 3576-3583.
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Ilya D. Gridnev,* Alexander Zherebker,
Yuri Kostyukevich, Eugene Nikolaev
Page No. – Page No.
Methylene Group Transfer in
Carbonyl Compounds Discovered in
Silico and Detected Experimentally
Previously unknown transformation of aldehydes, ketones and carboxylic acid
derivatives leads to the formation of substituted oxiranes, aziridines and azirines as
shown by DFT and MP2 computations and proved experimentally by electrospray
ionization mass-spectrometry with heated desolvating capillary.
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