Direct amidation of acid fluorides using germanium amides

Article abstract of DOI:10.1039/d1dt00754h

Amide functional groups are an essential linkage that are found in peptides, proteins, and pharmaceuticals and new methods are constantly being sought for their formation. Here, a new method for their preparation is presented where germanium amides Ph₃GeNR₂convert acid fluorides directly to amides. These germanium amides serve to abstract the fluorine atom of the acid fluoride and transfer their amide group -NR₂to the carbonyl carbon, and so function as amidation reagents.

Full text of DOI:10.1039/d1dt00754h

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Direct amidation of acid fluorides using
germanium amides†
Cite this: Dalton Trans., 2021, 50,
4490
Ardalan Hayatifar, Emily A. Elifritz, Molly B. Bloom, Kaitlyn M. Pixley,
Received 6th March 2021,
Accepted 19th March 2021
Christopher J. Fennell and Charles S. Weinert
*
DOI: 10.1039/d1dt00754h
rsc.li/dalton
Amide functional groups are an essential linkage that are found in
Recently, it was shown that germylium ions are fluorophilic
3
0,31
peptides, proteins, and pharmaceuticals and new methods are in nature.
Specifically, the germane Ph GeH was found to
3
constantly being sought for their formation. Here, a new method replace the fluorine atom with a hydrogen atom in acid fluor-
for their preparation is presented where germanium amides ides and aliphatic organofluorine compounds, and this occurs
+
+
Ph
3 2
3 3 3
GeNR convert acid fluorides directly to amides. These germa- by the formation of the Ph Ge ion from Ph GeH by the Ph C
nium amides serve to abstract the fluorine atom of the acid ion. This raised the question as to whether or not germylium
fluoride and transfer their amide group –NR
2
to the carbonyl cations could be employed for the conversion of acid fluorides
carbon, and so function as amidation reagents.
to amides.
3 2
The reaction of Ph GeH in the presence of an amine HNR ,
an acid fluoride, and a salt of the tritylium cation as shown in
Scheme 2A is not a feasible method for the formation of an
Aryl and alkyl amides are highly significant moieties in chem-
istry and biochemistry, as they form important linkages in pep-
tides, proteins, pharmaceuticals, natural products and other
amide, because even very weak Lewis bases significantly
1
–6
types of molecules. Because of their significance, amidation
reactions are highly studied and new methods to carry out this
+
diminish the electrophilicity of the germylium ion Ph Ge .
3
However, it was found that germanium amides can react
7
,8
transformation are constantly being sought.
Of particular
directly with acid fluorides to yield an amide and Ph
Scheme 2B).
The successful formation of the amide from the germa-
3
GeF
interest are green methods of synthesis that have good atom
(
9
economy, and one of the main driving forces for the develop-
ment of new synthetic methods for amides is their importance
in pharmaceuticals since three quarters of potential medicinal
reagents have this linkage somewhere within their
nium amide suggested that the germanium atom in germa-
nium amides must be somewhat Lewis acidic. In order to
determine if this is the case, the Lewis acidity of the germa-
1
0,11
structure.
nium amide Ph
Beckett method.
3
GeNMe
2
was assessed using the Gutmann-
Typical methods for the formation of amides involve the
use of carboxylic acids and a stoichiometric amount of a coup-
32,33
A benzene-d solution of Ph GeNMe was
6
3
2
31
treated with Et PO and the P NMR spectrum of the mixture
3
1
2–20
ling agent (Scheme 1A).
In addition, the transamidation
was recorded. The chemical shift for the phosphorus atom in
the mixture shifted downfield by 6.4 ppm from the resonance
of amides (Scheme 1B) or the amidation of esters (Scheme 1C)
has been employed to generate the amide functionality, and
these reactions can proceed in the presence or absence of tran-
2
1–28
sition metal catalysts.
The use of main group elements to
promote amide formation has been described as well,
although this is less common. For example, aluminium
amides were shown to be versatile reagents for the conversion
2
9
of esters to amides.
Department of Chemistry, Oklahoma State University, 107 Physical Science,
Stillwater, Oklahoma 74078, USA. E-mail: charles.s.weinert@okstate.edu
†
Electronic supplementary information (ESI) available: Experimental pro-
cedures, NMR spectra, LC/MS and HRAM-MS data for the amidation reactions.
See DOI: 10.1039/d1dt00754h
Scheme 1 Amidation reactions of carboxylic acids and carboxylic acid
derivatives.
4490 | Dalton Trans., 2021, 50, 4490–4493
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by silica gel chromatography, and the purified products were
characterized by NMR spectroscopy and GC/MS by comparison
of these data to those of commercially available amides. The
Ph GeF byproduct can also be isolated by silica gel chromato-
3
graphy, and this can be converted back to the germanium
amide reagents by salt metathesis with the corresponding
2
amide LiNR’ in greater than 90% yield. Therefore, this
process is atom efficient and also cost effective.
The identities of the pure amide products 1–6 were further
confirmed using high resolution accurate mass mass spec-
Scheme 2 Potential amidations of acid fluorides by germanium trometry (HRAM-MS). The HRAM-MS spectrum of 1 is shown
amides.
in Fig. 1 and the error between the experimental and theore-
tical data is 0.7 ppm. The errors for the other five products
range from 0.05–8.64 ppm and so all of the HRAM-MS experi-
mental data match extremely well with the calculated spectra
confirming the composition of the reaction products.
for Et
is weakly Lewis acidic.
The successful conversion of four acid fluorides to their
corresponding amides using germanium amides Ph GeNR’ is
shown in Scheme 3. Slow addition of the germanium amide to
a benzene solution of the acid fluoride followed by refluxing
3 3 2
PO, indicating that the germanium atom in Ph GeNMe
It is also possible to carry out a deoxyfluorination and ami-
dation reaction in a manner similar to that of Prakash and co-
3
2
3
6
workers as shown in Scheme 4. Treatment of a solution of
benzoic acid with PPh and N-bromosuccinimide, followed by
3
for 6 h resulted in the formation of the amide and Ph
3
GeF.
the addition of tetrabutylammonium fluoride resulted in the
These reactions also proceed to completion at room tempera-
formation of benzoyl fluoride in situ, which was confirmed by
1
9
1
9
ture in 18 h. The presence of Ph
3
GeF was confirmed using
F
the presence of a resonance at δ 18.1 ppm in the F NMR
1
9
NMR spectroscopy, as the signature resonance at
δ
spectrum of the reaction mixture. The F NMR spectrum also
3
1,34,35
31
−202.4 ppm was observed.
indicated the formation of HF and Ph
3 2
PF , while the P NMR
The conversions of the acid fluorides to amides were
spectrum indicated the formation of Ph PO. Subsequent
3
1
13
19
greater than 99% as shown by NMR ( H, C, and F) spec-
troscopy. The formation of the desired amide products was
further confirmed using GC/MS. Pure amides could be isolated
3 2
addition of 1.1 eq. of Ph GeNMe resulted in the formation of
1
as shown by NMR spectroscopy and LC/MS, and 1 was iso-
lated from the reaction mixture in 50% yield.
In order to probe the reaction pathway to determine how
the amide group transfer might be proceeding, a kinetic ana-
lysis was carried out by monitoring the rate of disappearance
Fig. 1 Experimental HRAM-MS (top) and calculated HRAM-MS (bottom)
of 1.
Scheme 3 Amidation reactions of acid fluorides by germanium amides.
Scheme 4 One pot conversion of benzoic acid to 1.
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of benzoyl fluoride with time using F NMR spectroscopy. silicate ([(Me
Dalton Transactions
1
9
2
N)
3
S][Me
3
SiF
2
], TASF), which is a strong fluori-
Plots of the [PhCOF] versus time, ln [PhCOF] versus time, and nating agent. When an equimolar amount of TASF and
1
9
1
3 2
/[PhCOF] versus time indicated that the latter process gave the Ph GeNMe are combined, a resonance in the F NMR spec-
best linear fit. Therefore, the reaction pathway shows a second trum of the product mixture was observed at δ −125.0 ppm
order process in PhCOF and this indicates that an associative that is in the range for pentavalent germanates including
−
−
reaction pathway is occurring.
3 2 2 2
[Ph GeF ] (ref. 34) and [PhMe GeF ] (ref. 34 and 40) that
To shed further light on the reaction pathway, the transition have peaks at δ −118.9 and − 126.4 ppm, respectively. The
state of the reaction was calculated for four different possible resonance at δ −125.0 ppm is assigned to the [Ph Ge(F)
3
3
7
−
2
pathways by DFT using B3LYP/cc-pVTZ basis set as shown in NMe ] anion. Signals at δ −157.1 and −202.4 ppm are also
4
1
31
Fig. 2. The data indicate that the amidation of the acid fluoride indicative of the formation of Me
3
SiF
3
and Ph GeF,
occurs via a Sigma bond metathesis process rather than by an respectively.
ionic pathway involving abstraction of the fluorine by the ger-
manium amide to form a five coordinate germyl anion or by Ph
The reaction of Ph
3
GeNMe
2
with TASF suggests that
GeN(SiMe are fluorophilic
i
3
GeNMe
2
, Ph
3
GeNPr
2
, and Ph
3
3 2
)
dissociation of the -NMe2 moiety from the germanium. In and this was further confirmed by computing their fluorine
addition, the energy of the transition state is low at +6.48 kJ ion affinities (FIA) using DFT. The FIA values for Ph GeNMe
are 210, 202, and 225 kJ
readily at room temperature. An intrinsic reaction coordinate mol , indicating that Ph GeN(SiMe ) is the most fluorophilic
3
2
,
−
1
i
3 2 3 3 2
mol , which explains why the reaction is facile and proceeds Ph GeNPr , and Ph GeN(SiMe )
−
1
3
3 2
(
IRC) calculation following the identification of the transition of the three germanium amides. These values are higher than
state shows that the energy decreases along the transition state those for the germanes GeH , GeMe , and GePh that are 111,
vibrational mode in both the forward and reverse directions. 107, and 188 kJ mol− , respectively, but are less than the FIA
The greater decrease in the forward direction is supportive of values for the halogermanes GeF and GeCl that are 353 and
the products being more thermodynamically stable than the 314 kJ mol− , respectively. Therefore, the presence of the –NR
reactants and also of the expected heat evolved during the substituent versus an alkyl or aryl substituent increases the
course of the reaction. fluorophilicity of the germanium atom in germanium amides
The reaction pathway is consistent with the Wiberg Bond by a significant extent.
4
4
4
1
4
4
1
2
3
8,39
Indices (WBI)
tures of Ph GeNMe
again using the B3LYP/cc-pVTZ basis set. In Ph
that were calculated for the optimized struc-
In conclusion, it is evident that germanium amides
GeNR function as reagents for a previously unknown but
2
the viable method for the formation of amide reagents. These
i
3
2
, Ph
3
GeNPr
2
, and Ph
3
3
GeN(SiMe
3
)
2
by DFT Ph
3
2
7
3
GeNMe
electron density is distributed 79.3% on nitrogen and 20.7% reagents abstract the fluorine atom of acid fluorides and
on germanium. The electron density is distributed more transfer their amide group to the acid fluoride by a sigma
highly on the nitrogen atom among the three germyl amines bond metathesis reaction. Germanium amides having
i
in the order R = Me < Pr < SiMe indicating that the inductive different organic substituents at the nitrogen and/or germa-
3
effects of the substituents at the nitrogen atom affects the elec- nium atoms might function as amidation reagents for the
tron distribution in the Ge–N bond.
synthesis of a variety of amides. The scope of this intercon-
The fluoride affinity of Ph GeNMe was investigated experi- version, as well as its pathway, will be studied in further
3
2
mentally by reacting it with trissulfonium difluorotrimethyl- detail.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by a grant from the National
Science Foundation (CHE-1464462) and is gratefully
acknowledged. The computing for this project was per-
formed at the OSU High Performance Computing Center at
Oklahoma State University supported in part by the National
Science Foundation grant OCI-1126330. The authors wish to
thank Prof. Steve Hartson (Department of Biochemistry and
Molecular Biology, Oklahoma State University) for his
patient assistance in acquiring the HRAM-MS data for this
work.
Fig. 2 Transition state of the amidation reaction calculated using DFT.
Gibbs energies are given in units of kJ mol−
1
.
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