Vanadium(v) oxoanions in basic water solution: A simple oxidative system for the one pot selective conversion of l-proline to pyrroline-2-carboxylate

Article abstract of DOI:10.1039/c7dt02702h

The unprecedented, direct chemical oxidation of l-proline to pyrroline-2-carboxylate was achieved in water (pH 9-10) by means of NH₄VO₃/NH₃ or V₂O₅/MOH (K = Na, K), and the anion was fully characterized as ammonium or alkaline metal salts. Quantitative yield and higher atom economy performance were achieved with the latter system, the alkaline salts being more stable than the ammonium one. Different mixed valence V(iv)/V(v) compounds precipitated from the reaction mixtures depending on the nature of the employed base. A possible reaction mechanism is proposed according to DFT calculations. The analogous reaction of trans-4-hydroxy-l-proline with NH₄VO₃/NH₃ afforded pyrrole-2-carboxylic acid in 81% yield, while sarcosine underwent prevalent decomposition under similar experimental conditions. Instead, no reaction was observed with primary (glycine, l-alanine, l-phenylalanine) and tertiary α-amino acids (N,N-dimethyl-l-phenylalanine, N,N-dimethylglycine).

Full text of DOI:10.1039/c7dt02702h

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Efficient extraction of sulfate from water using
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Vanadium(V) Oxoanions in Basic Water Solution: a Simple Oxidative System for the
One Pot Selective Conversion of ꢀProline to Pyrrolineꢀ2ꢀCarboxylate
L
Lorenzo Biancalana,a Giada Tuci,a Fabio Piccinelli,b Fabio Marchetti,a,$ Marco Bortoluzzi,c,* and Guido Pampaloni a,
*
a
University of Pisa, Dipartimento di Chimica e Chimica Industriale, Via G. Moruzzi 13, Iꢀ56124 Pisa, Italy. Tel: +39 050 2219245. Eꢀmail:
guido.pampaloni@unipi.it. Webpage: http://www.dcci.unipi.it/guidoꢀpampaloni.html.
b University of Verona, Solid State Chemistry LaboratoryꢀDB, Strada le Grazie 15, 37134, Verona, Italy
c Ca’ Foscari University of Venice, Dipartimento di Scienze Molecolari e Nanosistemi, Via Torino 155, Iꢀ30175 Mestre (Venezia), Italy
This submission was created using the RSC Article Template (DO NOT DELETE THIS TEXT)
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The unprecedented, direct chemical oxidation of Lꢀproline to pyrrolineꢀ2ꢀcarboxylate was achieved in water (pH 9ꢀ10) by means of NH4VO3/NH3
or V2O5/MOH (K = Na, K), and the anion was fully characterized as ammonium or alkaline metal salts. Quantitative yield and higher atom
economy performance were supplied with the latter system, the alkaline salts being more stable than the ammonium one. Different mixed valence
V(IV)/V(V) compounds precipitated from the reaction mixtures depending on the nature of the employed base. A possible reaction mechanism is
proposed according to DFT calculations. The analogous reaction of transꢀ4ꢀhydroxyꢀ
Lꢀproline with NH4VO3/NH3 afforded pyrroleꢀ2ꢀcarboxylic
acid in 81% yield, while sarcosine underwent prevalent decomposition under similar experimental conditions. Instead, no reaction was observed
with primary (glycine, Lꢀalanine, Lꢀphenylalanine) and tertiary αꢀamino acids (N,NꢀdimethylꢀLꢀphenylalanine, N,Nꢀdimethylglycine).
Introduction
αꢀImino acids are intermediates in the Strecker degradation of αꢀamino
acids (see Scheme 1).1 This decarboxylative oxidation process is
promoted by a variety of inorganic and organic agents and plays a key
role in food chemistry.2 As a direct consequence, αꢀimino acids are
relatively unstable substrates and only a few of them have been
isolated.3
O
O
H2O
R
<ox>
R
R
Scheme 2. Overview of oxidation reactions of
Lꢀproline.
+ CO2 + NH3
O
OH
O
NH3
NH
A selective dehydrogenation at the CH−NH position of
L
ꢀProline
Strecker aldehyde
-amino acid
-imino acid
without undesirable side reactions (such as decarboxylation and overꢀ
oxidation of the product) was achieved only using protecting strategies
on the αꢀamino acid. For instance, sodium pyrrolineꢀ2ꢀcarboxylate has
Scheme 1. The Strecker degradation of a generic primary αꢀamino acid.
Among this class of compounds, pyrrolineꢀ2ꢀcarboxylic acid, HP2C
(conjugate base: pyrrolineꢀ2ꢀcarboxylate, P2C─) has aroused interest
for its biochemical role 4 and utility in organic synthesis.5 This αꢀimino
acid has been obtained in solution by the cyclization of 5ꢀaminoꢀ2ꢀ
oxopentanoic acid in water6 or its NꢀC(=X)NH2 derivatives (X = O,
NH) in trifluoroacetic acid.7 However, it is more desirable to obtain
been isolated with a fiveꢀstep synthesis involving the preparation of Lꢀ
Proline methyl ester, oxidation with tBuOCl and final basic hydrolysis
of the ester.5 A second multistep synthesis of the sodium salt Na[P2C]
has been reported, involving coordination of
Lꢀproline to Cu(II),
oxidation of the coordinated ligand by MnO2/H2O2 and dissociation of
the αꢀimino acidate ligand performed with an anionꢀexchange resin.13
The possible use of transition metals as “protecting groups” for this
synthesis is limited by the fact that pyrrolineꢀ2ꢀcarboxylate is a good
N,Oꢀchelating ligand14 and it is therefore difficult to dissociate from
the metal centre at the end.
In the light of the possible roles played by vanadium in living
organisms,15 the interaction of vanadium ions with αꢀamino acids and
oligoꢀpeptides in water medium has aroused a considerable attention.16
However, vanadium(V) is known to exhibit a poor affinity towards αꢀ
amino acids in aqueous solution17 (unless peroxo18 or hydroxylamido19
ions are present) and only one (not fully characterized)
oxovanadium(V)ꢀamino acid complex has been isolated so far.20
Moreover, the orthovanadate ion, [VO4]3─, is isoelectronic with other
oxoꢀmetallate ions of the first transition series, such as [MnO4]─ and
[CrO4]2─, but the former is featured by a significantly lower
electrochemical reduction potential (see Table S1 given as Supporting
Information). Therefore, we reckoned that vanadium(V) was an
interesting candidate in order to explore its oxidation chemistry
towards αꢀamino acids.
P2C─ from a cheap and natural starting material such as
Lꢀproline.
To the best of our knowledge, the direct conversion of
L
ꢀProline to
P2C─ has been achieved only via enzymatic routes (Scheme 2).8 In
fact, classic Strecker degradation agents, such as ninhydrin or 1,2ꢀ
dicarbonyl compounds, do not react with Lꢀproline as well as other
secondary amino acids.1 On the other hand, the oxidation of
LꢀProline
by organic oxidants, such as Nꢀbromosuccinimide in water9 or
iodosylbenzene in various solvents,10 yields 2ꢀpyrrolidinone. The same
product has been obtained by treatment of
aqueous H2SO4 (pH = 2).11 Alkaline KMnO4 reacts with
affording 4ꢀaminobutanal, i.e. the corresponding Strecker aldehyde.12
Lꢀproline with NaIO4 in
LꢀProline
1

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In this paper, we report on the reactions of a series of αꢀamino acids
with V(V) species in alkaline medium, providing a route for the one
pot proline to pyrrolineꢀ2ꢀcarboxylate conversion.
the salt in the solid state.
+
These drawbacks were overcome by cation exchange, from NH4 to
Na+ or K+. In fact, the quantitative formation of M[P2C] (M = Na, K)
was achieved when 2:1 mol/mol mixtures of V2O5 and Lꢀproline were
treated with MOH up to pH = 10 and then heated at reflux temperature
for 67 or 90 hours, respectively (Scheme 3b).
Results and Discussion
Sodium and potassium pyrrolineꢀ2ꢀcarboxylate could be isolated as
ivoryꢀwhite crystalline materials in low to moderate yields, allowing
Conversion of
optimization and solid state isolation of M[P2C], M = Na, K.
Ammonium vanadate was initially studied as commercially
available, possible oxidative agent respect to ꢀproline. Thus, when
mixtures of NH4VO3 and ꢀproline in water were treated with
Lꢀproline to pyrrolineꢀ2ꢀcarboxylate: reaction
1
the full spectroscopic characterization of the anion (IR, UVꢀVis, H
and 13C NMR). To the best of our knowledge, the potassium salt is
unprecedented, while Na[P2C] was previously obtained only by multiꢀ
step synthetic protocols.5,13
a
L
L
The black precipitates, filtered off at the end of the reaction, were
identified as V(IV)ꢀV(V) species NaV2O5 (XRPD). spectroscopic and
analytical techniques) and K2V3O8 (spectroscopic and analytical
techniques), respectively. The observed XRPD pattern corresponding
to NaV2O5 is shown in Figure 1.
ammonia and heated at 70°C for 24ꢀ48 hours, a redox reaction took
place. The resulting dark coloured solutions were investigated by
NMR
spectroscopy,
revealing
the
selective
oxidation
(dehydrogenation) of
L
ꢀproline to the corresponding αꢀimino acidate
(P2C─), Scheme 3a. The black precipitate, separated by filtration, was
characterized by XRPD, which indicated the presence of the mixedꢀ
valence V(V)ꢀV(IV) salt (NH4)2V3O8 in mixture with unreacted
NH4VO3 (see Figure S1).
Scheme 3. V(V)ꢀmediated one pot conversion of Lꢀproline to pyrrolineꢀ2ꢀ
carboxylate (P2C─).
Figure 1. Xꢀray powder diffraction pattern of the black precipitate from the
The formation of P2C─ in the NH4VO3/NH3/
Lꢀproline system was
investigated by varying the ratios between the reactants (see
Experimental and Table S2).
reaction of V2O5 with
Lꢀproline in aqueous NaOH solution at pH = 10.
Reference PDF card from ref. 22.
It should be noted that the initial pH of reaction mixtures was not
measured: the pH value varied over time due to the progressive
dissolution of NH4VO3 (not completely soluble under the selected
conditions) and the progress of reaction (see SI). Therefore,
representative pH values corresponding to a given NH3/NH4VO3
molar ratio were determined by NH3 titration of a dilute solution of
NH4VO3 (Figure S2). The redox process occurred only within a
limited window of pH values (modified via the NH3/NH4VO3 ratio);
this fact may be related to the pHꢀdependent speciation of vanadates in
solution.Error! Bookmark not defined.b,21
To the best of our knowledge, the reactions reported in Scheme 3
represent the first example of direct chemical oxidation of Lꢀproline to
pyrrolineꢀ2ꢀcarboxylate, avoiding the use of groupꢀprotecting
strategies. It is worthy to note that, in every cases, vanadium
complexes with either L
ꢀproline or P2C─ were not detected in solution
or in the solid state, thus confirming the reluctance of vanadates to
bind monoanionic N,O ligands (see Introduction).17
Indeed, 51V NMR spectroscopy was employed to identify V(V)
species in solution under the experimental conditions described above
for the L
ꢀProline/NH3VO4 reaction (see SI). The anions [HVO4]− and
The optimal reaction parameters were established to be
NH3/NH4VO3 ratio = 1 (corresponding to pH = 9.4 for a dilute
[HV2O7]3− were identified in the early stages of reaction, followed by
the appearance of a third signal, ascribable to tetravanadate ions
(cyclic [V4O12]4− or linear [V4O13]6−) which became predominant as
solution), NH4VO3/Lꢀproline ratio = 4 and vanadium loading = 1.0
mol L−1 (see Table S2 for details). Assuming (NH4)2V3O8 as the
only vanadium product, the stoichiometry requires six V(V) ions
the oxidation of Lꢀproline progressed (Figure S4). Reduction potentials
for a relevant V4(V)/V4(IV) couple in the investigated pH range are
included in the Supporting Information.
per Lꢀproline, two of them undergoing reduction to V(IV) and the
other four being incorporated within (NH4)2V3O8 (Equation 1). A
partial aerobic reꢀoxidation of V(IV) to V(V) may account for the
discrepancy between theoretical (6) and experimental (4) value of
A series of oxidants have been reported to promote the oxidation of
proline to products different from P2C─ (see Introduction). In order to
expand the knowledge on the oxidation chemistry of ꢀproline in
Lꢀ
L
the optimal NH4VO3/Lꢀproline ratio.
water, and to see the possibility of performing the transformation to
P2C─ by oxidant species alternative to V(V), H2O2 and Ce(SO4)2 were
tested under similar experimental conditions. While no reaction
6 NH4VO3 + C5H9NO2 → (NH4)[C5H6NO2] + NH3 +
2 H2O + 2 (NH4)2V3O8
(1)
occurred in the presence of cerium(IV) sulfate, the reaction of Lꢀ
proline with hydrogen peroxide gave a 81/19 mixture of succinimide
and succinic anhydride (Scheme 4). This outcome reinforces the idea
Under the optimized conditions, a P2C─ yield of 55% in solution was
obtained after 25 h at 70°C (entry #14 in Table S2). However, the
thermal and vacuum instability of ammonium pyrrolineꢀ2ꢀcarboxylate
prevented the yield from reaching higher values, and the isolation of
that V(V) holds unique features so to make possible the direct
Lꢀ
proline to P2C─ conversion.
2

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by a OH─ ligand. On the other hand, in Cꢀis2 the organic frame
maintains its radical character and only one V(IV) centre is present in
the polyoxovanadate.
The formation of C from B is accompanied by a strongly negative
Gibbs energy variation, −34.7 kcal molꢀ1. A detailed investigation of
the geometry optimization steps affording C suggests that a water
molecule takes part to the proton transfer. The coordination mode by
the carboxylate group is the same as that described for the
intermediates A and B.
Scheme 4. Oxidation reaction of Lꢀproline with H2O2.
ꢀProline to P2C─ conversion: DFT study.
L
The simple dissociation of the ligand from the polyoxo anion is not
favourable, but the P5C─ anion may be displaced by water to form D
(Figure 2). Even if the simple reaction depicted in Figure 2 has
positive ꢀG, we must consider the concentration of water, the alkaline
pH and therefore the presence of OH− ions as good nucleophiles, and
the decomposition of the final mixedꢀvalence compound to unsolvable
species as presumable driving forces. The tautomerization of
pyrrolineꢀ5ꢀcarboxylate to the final pyrrolineꢀ2ꢀcarboxylate is
favourable by about 3.5 kcal molꢀ1.
Possible intermediates in the selective oxidation of Lꢀproline by V(V)
were studied by means of DFT calculations, considering water as
continuous medium. One H2O molecule was explicitly added to the
computational models.
According to 51V NMR spectroscopy, polynuclear V(V) oxoꢀanions
may be generated in water under the experimental conditions
described above (see Figures S3 and S4),21 and a model based on four
vanadium centres (cyclic tetravanadate) was chosen to balance the
computational requests and the reliably of the simulations.
All the attempts to computationally obtain coordination compounds
L
ꢀproline and [V4O12]4─ or
Figure 2 about here
between the conjugate base of
[V4O11(OH)]3─ were unsuccessful because of the electrostatic
Figure 2. DFTꢀoptimized structures of possible intermediates involved
in the oxidation of Lꢀprolinate to pirrolidineꢀ2ꢀcarboxylate and relative
repulsion between Lꢀprolinate and the anions. On the other hand, a
complex was obtained using [V4O10(OH)2]2─ as a reactant. It has to be
highlighted that the protonation of the tetravanadate [V4O12]4─ up to
[V4O10(OH)2]2─ is thermodynamically viable from preliminary DFT
calculations, while the formation of [V4O9(OH)3]– is unlikely in basic
solution.23
Gibbs energy values (kcal molꢀ1, T = 343.15 K). CꢀPCM/ωB97X
calculations, water as continuous medium. Colour map: light grey,
hydrogen; dark grey, carbon; red, oxygen; blue, nitrogen; green,
vanadium, light blue, spin density surface (isovalue = 0.01 a.u.).
Cartesian coordinates of the DFTꢀoptimized structures are collected in
a separated. xyz file.
The generation of [V4O10(OH)2(
L
ꢀprolinate)H2O]3─ (A, Figure 2) from
ꢀprolinate is favourable, being the
[V4O10(OH)2ꢁH2O]2─ and
L
corresponding Gibbs energy variation about −11.8 kcal molꢀ1 at 343.15
K, which is the temperature adopted for the reaction with
NH4VO3/NH3. The optimized geometry of A is shown in Figure 2.
The coordination involves the carboxylate moiety, which is κ1ꢀbonded
to a vanadium centre. The V−Ocarboxylate distance is 2.056 Å. The
Substrate scope and mechanistic investigation.
Considering the results described in the previous paragraph, we
were interested to see whether the observed V(V)ꢀoxidation of
proline could be extended to other αꢀamino acids. Therefore, a
series of αꢀamino acids (Scheme 5) were allowed to react with
interaction of
Lꢀprolinate with the metal anion is enforced by a
NH4VO3 under the conditions optimized for
eq. NH4VO3, 70 °C, 40 h). No reaction was observed with αꢀamino
acids having tertiary amino groups (N,NꢀDimethylꢀ
Lꢀproline (4 eq. NH3, 4
hydrogen bond between the other oxygen atom of the carboxylate
group and a bridging hydroxo ligand (OcarboxylateꢀꢀꢀH, 1.565 Å; O−H,
1.007 Å). On the other hand, the NH fragment does not appear
involved in any meaningful interaction. The cyclic structure of the
polyoxovanadate is maintained after coordination, even though one
vanadium centre is fiveꢀcoordinated.
Lꢀ
phenylalanine, N,Nꢀdimethylglycine), as expected since C=N bond
formation for these substrates would imply the breaking of carbonꢀ
nitrogen bonds. On the other hand, reaction mixtures of secondary
αꢀamino acids (Nꢀmethylglycine (sarcosine), transꢀ4ꢀhydroxyꢀ
proline) rapidly turned black followed by the precipitation of
(NH4)2V3O8 as found for ꢀproline (Scheme 3a). Pyrroleꢀ2ꢀ
carboxylic acid was isolated in 81% yield from transꢀ4ꢀhydroxyꢀ
Lꢀ
The most likely subsequent intermediate involves the oneꢀelectron
transfer from coordinated Lꢀprolinate to the polyoxo anion, to obtain
L
the triplet state geometry B depicted in Figure 2. The Gibbs energy
variation is only slightly positive, around 5.9 kcal molꢀ1. The presence
L
ꢀ
proline after acidification of the reaction mixture with HCl and
subsequent Et2O extraction (Scheme 5b). This product was
of a V(IV) centre, bound to Lꢀprolinate, is confirmed by the spin
density surface shown in Figure 2. The amino acidate ligand has
radical character, and the unpaired electron is mainly localized on the
nitrogen atom. The coordination mode of the amino acidate is
comparable to that already described for intermediate A, but it has to
be remarked that the oxidation of the ligand is accompanied by
hydrogen migration from the nitrogen atom to one of the oxoꢀligands,
converting into a terminal hydroxo.
previously obtained by the oxidation of transꢀ4ꢀhydroxyꢀLꢀproline
with CuSO4/H2O2.24 The formation of the aromatic pyrrole ring is
probably the driving force for the dehydrogenationꢀdehydration of
the αꢀamino acid. On the other hand, the oxidation of sarcosine by
NH3/NH4VO3 was not selective, yielding methylammonium and
−
several unidentified species deriving from the [CH2CO2 ] fragment
(Scheme 5c). DFT calculations indicate that the coordination mode
of the sarcosinate anion to [V4O10(OH)2ꢁH2O]2ꢀ should be
analogous to that discussed for Lꢀprolinate (see Figure S6).
Another hydrogen migration from Lꢀprolinate to the polyoxovanadate,
in particular from the Nꢀbonded CH2, could afford intermediate C
(Figure 2). The hydrogen migration from the CH2 group causes the
conversion of another oxoꢀligand to a terminal hydroxo. The hydrogen
atoms of such methylene group are expected to be acidic due to their
Surprisingly, reaction attempts involving primary αꢀamino acids
(glycine,
Lꢀalanine, Lꢀphenylalanine) led to clean recovery of the
starting materials (Scheme 5a).
closeness to the electronꢀpoor nitrogen. Deprotonation of
alpha position appears less probable because of the relative orientation
of the ꢀprolinate ligand with respect to the polyoxometalate skeleton.
Lꢀprolinate in
L
More importantly, the resulting complex (intermediate Cꢀis2, see
Figure S5) is much less stable than intermediate C, by about 41.4 kcal
mol−1 both at 298 K and 343 K. This result can be explained on the
basis of the spin density surfaces of C and Cꢀis2, depicted in Figure
S5. The hydrogen migration affording C is accompanied by a second
electron transfer, and the product is a pyrrolineꢀ5ꢀcarboxylate (P5C─)
complex of a polyoxovanadate containing two V(IV) centres, bridged
3

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different, and that hydrogen bonding may play a key role in the
formation of pyrrolineꢀ2ꢀcarboxylate.26 Another indication in this
sense was obtained by using Et3N as a base: no reaction between V2O5
and Lꢀproline occurred after 40h at 70°C, while MOH/V2O5/Lꢀproline
mixtures (M = Na, K) gave a quantitative conversion to P2C− (Scheme
3B).
Conclusions
The interaction of vanadium ions with αꢀamino acids has aroused a
great interest due to possible biological implications, and vanadium(V)
was found to exhibit a poor affinity towards these biologically relevant
compounds. This aspect, combined with the peculiar reduction
potential of V(V) species, allows to selectively achieve the unusual,
Scheme 5. V(V)ꢀmediated conversion of b) transꢀ4ꢀhydroxyꢀLꢀproline
to pyrroleꢀ2ꢀcarboxylate and c) sarcosine to methylammonium. No
reaction was observed with primary or tertiary αꢀamino acids (a).
one pot conversion of LꢀProline to the corresponding αꢀimino acidate,
using NH4VO3 or V2O5 as oxidants in basic water medium. The best
results, in terms of atom economy, yield and product stability, were
obtained with V2O5. It is remarkable that the straightforward V(V)
In order to find a possible explanation for the lack of reactivity of
primary αꢀamino acids, a DFT study was carried out by choosing
glycine as a representative compound. On theoretical grounds, the
coordination of glycinate to [V4O10(OH)2ꢁH2O]2ꢀ resembles that
mediated oxidation of LꢀProline is not reproducible with alternative
chemical oxidants, including H2O2, leading to different outcomes
(Scheme 6). Analogous amino acid to imino acid conversion was not
observed by allowing a series of αꢀamino acids to interact with
NH4VO3/NH3. The unique properties associated to Lꢀproline, among
the family of αꢀamino acid compounds,27 are probably responsible for
the specific outcome observed. However, vanadium(V) oxyanions in
basic aqueous solution were capable of reacting only with secondary
αꢀamino acids, primary and tertiary αꢀamino acids resulting to be
unreactive. It should be noted that most of the oxidizing agents
employed in the classical Strecker degradation of αꢀamino acids, either
are effective towards primary amino acids only, or do not show any
substrate selectivity.
described for Lꢀprolinate (Figure 3, intermediate E). Nevertheless,
the formation of the corresponding triplet state (intermediate F in
Figure 3) requires more energy (ꢀG = 12.6 kcal molꢀ1). More
important, the required, subsequent hydrogen migration may
involve only the alphaꢀcarbon and it is, differently from the case of
L
ꢀprolinate, not thermodynamically favourable (ꢀG = 3.5 kcal molꢀ
1). In the resulting species (intermediate G in Figure 3), the organic
ligand maintains its radical character, and only one metal centre
has been reduced to V(IV). In summary, the more difficult V(V)ꢀ
oxidation of glycinate with respect to prolinate is presumably at the
basis of the different reactivities observed with these two αꢀamino
acids.
Our results suggest the possible convenience in the use of simple and
cost effective V(V) compounds as stoichiometric oxidative agents for
exploring uncommon organic synthetic pathways.
Figure 3 about here
Figure 3. DFTꢀoptimized structures of possible intermediates in
the interaction of glycinate with [V4O10(OH)2ꢁH2O]2ꢀ and relative
Gibbs energy values (kcal molꢀ1, T = 343.15 K). CꢀPCM/ωB97X
calculations, water as continuous medium. Colour map: light grey,
hydrogen; dark grey, carbon; red, oxygen; blue, nitrogen; green,
vanadium, light blue, spin density surface (isovalue = 0.01 a.u.).
Cartesian coordinates of the DFTꢀoptimized structures are
collected in a separated .xyz file.
To shed more light on the mechanism of oxidation of secondary αꢀ
amino acids by V(V), the reactions with
Lꢀproline and transꢀ4ꢀ
hydroxyꢀ ꢀproline were then performed in D2O. In the case of Lꢀ
L
−
proline, 3,3ꢀdideuteroꢀ1ꢀpyrrolineꢀ2ꢀcarboxylate (P2Cꢀd2 ) was
NMR identified in solution at the end of the reaction. The
incorporation of deuterium in the C3 position of P2C− has been
previously observed and associated to a fast equilibrium occurring
between the cyclic imino and acyclic oxoꢀamino species in
Scheme 6. Overview of oxidation reactions of
discussed in this work).
Lꢀproline (in blue those
−
solution.25 However the yield of P2Cꢀd2 (35% after 30 h) was
significantly lower than that of P2C− under the same conditions
1
2
(55% after 25 h). The replacement of H with H in the O−H and
N−H bonds of the intermediates in Figure 2 caused negligible
changes of the relative energy values calculated by DFT (see
Figure S7). The slower rate of the reaction can be therefore
explained by supposing that, in the rateꢀdetermining transition
state, E−hydrogen bond breaking occurs, preceded by H/D
exchange.
Conversely, the reaction of transꢀ4ꢀhydroxyꢀLꢀproline in D2O afforded
pyrroleꢀ2ꢀcarboxylic acid, without incorporation of deuterium, in the
same yield as in the H2O experiment. These facts suggest that the
Experimental
a) General
All manipulations were performed in air with common laboratory
glassware. Reactions were carried out using deionised water. Solvents
and reagents, including αꢀamino acids, NH4VO3 (≥ 99%) and V2O5
(98%) were used as received from SigmaꢀAldrich. The stock solution
of NH3 (28% in H2O) was titrated with HCl before use. An Orion pHꢀ
meter equipped with a Hamilton glass pHꢀelectrode was used for pH
mechanism of oxidation of Lꢀproline and its 4ꢀhydroxy analogue are
4

Page 5 of 10
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT02702H
the solution: 4 mL). The mixtures were heated at 70°C with a reflux
condenser for 25ꢀ45 h yielding black suspensions. Comparable NMR yields
of P2C─ (50ꢀ60% after 20ꢀ30 h) were obtained when the amount of
NH4VO3 exceeded 1.0 mol·Lꢀ1 (see table S2, entries #10ꢀ13), as expected
for a saturated system. Therefore, we performed further reactions with a
vanadium loading of 1.0 mol·Lꢀ1.
measurements. The instrument was routinely calibrated with standard
pH = 2.0, 5.0 and 11.0 buffer solutions (Carlo Erba). Infrared spectra
(4000ꢀ650 cmꢀ1) were recorded at 298 K on a FT IRꢀPerkin Elmer
Spectrometer, equipped with a UATR sampling accessory. Spectra in
the 200ꢀ650 cmꢀ1 region were recorded in the transmission mode on
CsI tablets. UVꢀVis measurements were carried out at 298 K on a GE
Healthcare Ultrospec 2100 pro spectrophotometer, using 1 mm quartz
cuvettes in the 200ꢀ800 nm range. NMR spectra were recorded at 293
K on a Bruker Avance II DRX400 instrument equipped with a BBFO
broadband probe. The chemical shifts were referenced to the nonꢀ
deuterated aliquot of the solvent (1H and 13C) or to external standards
(51V to VOCl3). The 1H and 13C NMR spectra were assigned with the
assistance of DEPTꢀ135 and 1Hꢀ13C correlation experiments (gsꢀ
HSQC and gsꢀHMBC).28 A sealed capillary tube with C6D6 was used
when NMR analysis was performed on aliquots of the reaction mixture
in a nonꢀdeuterated media. In this case, NMR yield was estimated
from the relative intensity of 13C signals of analogous carbon atoms in
Temperature and time; 51V NMR monitoring. Reactions were performed
with NH4VO3 (4.0 mmol), 28% NH3 (NH3/V molar ratio = 1.0), LꢀProline
(V/Pro molar ratio = 4.0) and H2O (final volume of the solution: 4 mL).
The mixtures were heated at 70°C or 100°C with a reflux condenser
yielding black suspensions. At selected intervals the pH of the solution was
measured and aliquots were taken for 13C and 51V NMR analysis (see Table
S3 and Figure S4). The highest NMR yield (60%) was reached when
operating at 70°C for 46 h (see table S2, entries #14ꢀ15). Formation of byꢀ
products and a lower P2C─ yield (40°C) were observed for a longer reaction
time (67 h). No trace of P2C─ was found working at 100°C even for shorter
reaction times.
ii) Isolation of products in the optimized conditions.
The reaction was carried out with NH4VO3 (749 mg, 6.4 mmol), LꢀProline
the structure of the reactant (αꢀamino acid) and the product. In the Lꢀ
(184 mg, 1.6 mmol), 28% NH3 (6.5 mmol) and H2O (final volume of the
solution: 6.4 mL). The mixture was heated at 70°C with a reflux condenser
for 45 h. Therefore, the black suspension was allowed to cool to room
temperature and filtered. The black residue was washed with acetone and
dried under vacuum. This solid was identified by XRPD analysis as a
mixture of NH4VO3 and (NH4)2V3O8 (0.41/0.59 molar ratio, respectively).32
Yield: 626 mg, 90% with respect to the vanadium introduced. Anal. calcd.
for (NH4VO3)0.41((NH4)2V3O8)0.59: H, 2.73; N, 9.48; V(IV), 8.89; V(V),
38.42. Found: H, 2.68; N, 9.98; V(IV), 9.50; V(V), 38.0. IR (solid state): ν
= 3210mꢀbr, 3008mꢀbr, 2814mꢀbr, 1678w, 1652w, 1416s, 1262w, 993m
(VIV=O), 932s, 809s (VIVꢀOꢀVIV), 733s (VVꢀOꢀVV), 524w, 502w, 426m,
365m, 333w, 242w cm–1. Magnetic susceptivity: χg = 2.027×10–6 cm3—g–1;
ΣχmD = –102.5 ×10–6 cm3—mol–1; χmP = 5.78×10–4 cm3—mol–1; ꢂ = 1.16 ꢂB.33
All attempts to isolate ammonium pyrrolineꢀ2ꢀcarboxylate, NH4(P2C), from
the filtrate solution were unsuccessful.
Proline/pyrrolineꢀ2ꢀcarboxylate system, two analogous CH2 groups of
the cyclic structure were considered.29 Magnetic susceptibilities
(reported per V atom) were measured on solid samples at 298 K with a
Magway MSB Mk1 magnetic susceptibility balance (Sherwood
Scientific Ltd). Diamagnetic corrections were introduced according to
König.30 Melting points and decomposition temperatures were
determined on a STMP3 Stuart scientific instrument with a capillary
apparatus. Carbon, hydrogen, nitrogen analyses were performed on a
Carlo Erba mod. 1106 instrument. The vanadium(IV) and
vanadium(V) contents were determined according to the method
proposed by Mittal and Mehrotra.31
XꢀRay powder diffraction analysis (XRPD) were performed by a Thermo
ARL X´TRA powder diffractometer, operating in the BraggꢀBrentano
geometry and equipped with a Cuꢀanode Xꢀray source (Kα, λ =1.5418 Å),
using a Peltier Si(Li) cooled solid state detector. The patterns were collected
with a scan rate of 0.02 °/s in the 5°ꢀ90° 2θ range. The phase identifications
were performed with the PDFꢀ4+ 2015 database provided by the International
Centre for Diffraction Data (ICDD). Polycrystalline samples were ground in
a mortar and then put in a lowꢀbackground sample holder for the data
collection.
c) Reactions between V(V) ions (NH4VO3 as precursor) and αꢀamino
acids in aqueous ammonia solution.
General procedure. A suspension of NH4VO3 (4.0 mmol) in H2O was
treated with 28% NH3 (NH3/V molar ratio = 1.0), with the selected αꢀamino
acid (1.0 mmol, Vanadium/amino acid molar ratio = 4.0) and diluted with
H2O (final volume of the solution: 4.0 mL). The mixture was heated at
70°C with a reflux condenser for 40 h and analyzed by 13C{1H} NMR
spectroscopy.
b) Reactions between V(V) ions (NH4VO3 as precursor) and
in aqueous ammonia solution.
Lꢀproline
i) αꢀAmino acid = glycine, Lꢀalanine, Lꢀphenylalanine, N,NꢀdimethylꢀLꢀ
phenylalanine, N,Nꢀdimethylglycine. No reaction took place (colourless
solution + colourless solid). The starting material is the only species
identified in solution.
The determination of the optimum conditions for pH (as a function of the
NH3/V molar ratio) and the analysis of vanadium species in solution
through 51V NMR spectroscopy are given as Supporting information.
i) Optimization of the reaction conditions.
ii) αꢀAmino acid = sarcosine, transꢀ4ꢀhydroxyꢀLꢀproline. The mixture
darkened. At the end of the reaction, the black suspension was allowed to
cool at room temperature and filtered. The black residue was washed with
acetone and dried under vacuum. This solid was identified as a mixture of
NH4VO3 and (NH4)2V3O8, having identical IR spectrum with the product
NH3/V molar ratio. A suspension of NH4VO3 (8.4 mmol) in H2O was
treated with variable amounts of NH3 (NH3/V molar ratio = 0.1, 1.0, 2.1)
then with LꢀProline (2.1 mmol, V/Pro molar ratio = 4.0) and diluted with
H2O (final volume of the solution: 10 mL). Higher values of pH (12.2,
14.3) were obtained as follows: NH4VO3 (8.4 mmol) was suspended in
H2O, treated with NaOH until complete dissolution of the solid (pH = 14.3)
and diluted with H2O (final volume of the solution: 10 mL). The pH was
adjusted to 12.2 by adding the appropriate amount of 37% HCl. The
mixture was heated at 70°C with a reflux condenser for 40ꢀ65 h. When a
reaction took place, a black suspension was obtained within 1 h whose 13C
obtained with
Lꢀproline (section b/ii). Organic products were identified or
isolated as follows.
+
Sarcosine. The unreacted αꢀamino acid and CH3NH3 (13C{1H}: δ = 25.3
ppm, 65% NMR yield) were identified in solution. A number of low
intensity signals were observed, due to the extensive decomposition of the
carboxymethyl fragment of sarcosine. 13C{1H}: δ = 179.3, 177.0, 173.4,
171.1, 167.9, 166.4, 165.7, 164.0, 137.2, 65.5, 60.1, 58.6, 53.3, 43.4, 37.8,
35.4, 28.0 ppm.
NMR spectrum showed the resonances of
Lꢀproline (unreacted starting
material) and 1ꢀpyrrolineꢀ2ꢀcarboxylate (P2C─) anion [13C{1H}: δ = 175.8
(C=O); 171.9 (C=N); 60.3 (CH2ꢀN); 35.9 (CH2ꢀC=N); 22.0 (CH2ꢀCH2ꢀCH2)
ppm]. The highest NMR yield (40% after 45 h) was obtained with NH3/V
molar ratio = 1.0; no reaction was observed with a NH3/NH4VO3 ratio of
0.1 and when the pH was adjusted to ≥ 12 (see table S2, entries #1ꢀ5).
Transꢀ4ꢀhydroxyꢀLꢀproline. The pH of the filtrate solution was adjusted to
3 with 37% HCl. The aqueous phase was extracted with Et2O. Pyrroleꢀ2ꢀ
carboxylic acid was isolated as a colourless solid after solvent removal
under vacuum. Yield: 90 mg, 81%. IR (solid state): ν = 3351s, 3124wꢀm,
3007wꢀmꢀbr, 2918wꢀm, 2850wꢀm, 2700wꢀm, 2753wꢀm, 2624wꢀm, 2574wꢀ
m, 2514wꢀm, 2075vw, 1892vwꢀbr, 1654s, 1553mꢀs, 1436s, 1389mꢀs,
1323s, 1263m, 1187s, 1120vs, 1080m, 1034s, 947m, 878s, 845m, 749vs,
687mꢀs cm–1. 1H NMR (DMSOꢀd6): δ = 11.54 (s, 1H, COOH); 6.95 (dd,
1H, CHꢀNH); 6.73 (dd, 1H, CHꢀCꢀC=O); 6.14 (dd, 1H, CHꢀCHꢀCH) ppm.
13C{1H} NMR (DMSOꢀd6): δ = 162.7 (C=O); 124.1 (CHꢀNH); 123.1 (Cꢀ
C=O); 115.5 (CHꢀCꢀC=O); 110.0 (CHꢀCHꢀCH) ppm.
Vanadium/
NH4VO3 (6.4 mmol), 28% NH3 (NH3/V molar ratio = 1.0), variable
amounts of ꢀProline (V/Pro molar ratio = 1.0, 2.0, 4.0, 8.0) and H2O (final
LꢀProline molar ratio. Reactions were performed with
L
volume of the solution: 4 mL). The mixtures were heated at 70°C for 18ꢀ42
h with a reflux condenser yielding black suspensions. The formation of
P2C─ was observed in all cases; the highest NMR yield of P2C─ (60% after
31 h) was obtained by using a Vanadium/
table S2, entries #6ꢀ9).
Lꢀproline molar ratio of 4 (see
d) Reactions between V(V) ions (NH4VO3 as precursor) and αꢀamino
acids in ammonia D2O solution.
Vanadium concentration. Reactions were performed with variable
amounts of NH4VO3 (2.4, 4.0, 6.4, 8.0 mmol), 28% NH3 (NH3/V molar
ratio = 1.0), LꢀProline (V/Pro molar ratio = 4.0) and H2O (final volume of
5

Dalton Transactions
Page 6 of 10
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DOI: 10.1039/C7DT02702H
The general procedure followed is identical to that described in section c
except for the solvent (D2O). The Vanadiumꢀcontaining solid isolated from
these mixtures was identified as a mixture of ND4VO3 and (ND4)2V3O8.34
IR (solid state): ν = 3091vꢀwꢀbr, 2348mꢀwꢀbr (ND4+), 2222wꢀbr, 2135wꢀsh,
NMR (D2O): δ = 183.2 (succinimide, C=O); 177.5 (succinic anhydride,
C=O); 29.5 (succinimide, CH2); 29.2 (succinic anhydride, CH2) ppm.
Ce(SO4)2. A yellow solution of Lꢀproline (1.2 mmol) and Ce(SO4)2 (5.0
mmol) in H2O (5 mL) was heated at reflux temperature for 15 hours then
allowed to cool to room temperature. A sample of the solution was taken
+
+
2091wꢀsh (ND4 ), 1401vw, 1115vw, 1073mꢀw (ND4 ), 983m, 925wꢀm,
905w, 799s, 726s cmꢀ1.
for 13C NMR analysis, revealing only the presence of
Lꢀproline.
i) αꢀAmino acid =
Lꢀproline. The unreacted αꢀamino acid and 3,3ꢀ
─
dideuteroꢀ1ꢀpyrrolineꢀ2ꢀcarboxylate anion25 (P2Cꢀd2 ) were identified in
solution. NMR yield: 35% after 30 h. 13C{1H} NMR (D2O): δ = 175.7
(C=O), 171.9 (C=N), 60.3 (CH2ꢀN), 36.6ꢀ34.4 (m, CD2), 21.7 (CH2CD2)
ppm.
Computational Details
The computational geometry optimizations were carried out without
38
symmetry constrains, using the rangeꢀseparated DFT functional ωB97X,
in combination with the splitꢀvalence polarized basis set of Ahlrichs and
Weigend.39 The “unrestricted” formalism was applied for compounds with
unpaired electrons, and the lack of spin contamination was verified by
comparing the final <S2> values with the theoretical ones. The stationary
points were characterized by IR simulations (harmonic approximation),
from which zeroꢀpoint vibrational energies and thermal corrections (T =
298.15 K and 343.15 K) were obtained.40 The CꢀPCM implicit solvation
model was added to ωB97X calculations, considering water as continuous
+
ii) αꢀAmino acid = sarcosine. The unreacted αꢀamino acid and CH3ND3
were identified in solution. NMR yield: 35% after 76 h.
1H NMR (D2O): δ = 2.5 (s) ppm. 13C{1H} NMR (D2O): δ = 24.3 ppm.
iii) αꢀAmino acid = transꢀ4ꢀhydroxyꢀLꢀproline. Nonꢀdeuterated pyrroleꢀ2ꢀ
carboxylic acid was isolated as a colourless solid. Yield: 91 mg, 82%
(reaction time 63 h).
medium.41 The software used was Gaussian ’09.42 Preliminary DFT
e) Reactions between V(V) ions (V2O5 as precursor) and
basic aqueous solution.
LꢀProline in
43
calculations were carried out in vacuo with the EDF2
hybridꢀGGA
functional and the 6ꢀ31G** basis set, 44 using the Spartan '16 software. 45
package.
General procedure. A suspension of V2O5 (10 mmol) in H2O (20 mL) was
treated with ꢀproline (5.0 mmol, V/Pro molar ratio = 4) and the selected
L
base until pH = 10. The brownꢀgreen suspension was heated at a specified
temperature and analyzed by 13C{1H} NMR spectroscopy. Products were
identified or isolated as follows.
Supporting Information
i) NaOH as base. A dark suspension was obtained after 67 h at 100°C with
quantitative formation of P2C─ (13C NMR analysis). The reaction mixture
was allowed to cool to room temperature and filtered. The solid was
recovered by filtration, washed with water and dried in vacuo affording
black NaV2O5. The brown filtrate was added of acetone which caused the
precipitation of a pale brown solid (NaVO3) which was recovered by
filtration and dried in vacuo. The yellow filtrate solution was dried in vacuo
and the residue was reꢀdissolved in few mL of ethanol. Et2O addition
caused the precipitation of sodium pyrrolineꢀ2ꢀcarboxylate, Na(P2C), as an
ivory solid. The product was isolated by filtration, dried under vacuum and
stored under N2.
Detailed description of the determination of pH as a function of the
NH3/V molar ratio, Calculation of a plausible reduction potential
for the V(V)/V(IV) couple. Figures S1ꢀS6 and Table S1.
Acknowledgements
The University of Pisa is gratefully acknowledged for financial
support
NaV2O5. Identified by XRDP analysis and IR spectroscopy. Yield: 1,36 g,
66% with respect to the vanadium introduced. IR (solid state): ν = 1607w,
1412w, 1301vw, 992m, 963m, 916wꢀm, 875wꢀm cm–1.
NaVO3. Identified by XRDP analysis and IR spectroscopy.35 Yield: 750 mg,
31% with respect to the vanadium introduced. IR (solid state): ν = 1599w,
1416w, 960wꢀm, 929wꢀm, 869vs cm–1.
References and Notes
Na(P2C). Yield: 54 mg, 8%. Melting point: 255°C (decomposition). IR
(solid state): ν = 2951w, 2926w, 2867w, 1663vw, 1638w, 1606mꢀs (COO–),
1448w, 1409m (COO–), 1300m, 1257wꢀm, 1208w, 1155vw, 1134wꢀm,
1043w, 1009w, 988wꢀm, 915vw, 885vw, 780m, 723wꢀsh cm–1. 1H NMR
(D2O) δ = 3.77 (m, 2H, CH2ꢀN); 2.66 (m, 1.5H, CH2ꢀC=N)36; 1.85 (m, 2H,
CH2ꢀCH2ꢀCH2) ppm. 13C{1H} NMR (D2O) δ = 176.8 (C=O); 171.9 (C=N);
60.3 (CH2ꢀN); 35.9 (CH2ꢀC=N); 22.0 (CH2ꢀCH2ꢀCH2) ppm. UVꢀVis (H2O):
λmax (ε/L—cm–1—mol–1) = 205 (1.8—103), 252 (3.6—102), 307 (9.1—10) nm.
ii) KOH as base. A dark suspension was obtained after 90 h at 100°C with
quantitative formation of P2C─ (13C NMR analysis; 75% NMR yield after
67 h). From this reaction mixture, K2V3O8, KVO3 and potassium pyrrolineꢀ
2ꢀcarboxylate, K(P2C), were isolated as described in section eꢀi.
K2V3O8. Yield: 1.50 g, 62.5% with respect to the vanadium introduced. IR
(solid state): ν = 977m, 936m, 926m, 811s, 734s cm–1.
$
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KVO3. Identified by XRPD and IR analysis.37 Yield: 903 mg, 32.7% with
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Unreacted LꢀProline was the only species identified in solution.
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LꢀProline in aqueous solution.
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L
30% H2O2 (5 mL, 50 mmol) and then with NaOH until pH = 10. The
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room temperature. The aqueous solution was extracted with Et2O and the
organic phase was dried in vacuum. The residue was identified as a mixture
of succinimide (81%) and succinic anhydride (19%) by NMR analysis. IR
(solid state): ν = 2934wꢀm, 2533w, 2251wꢀm, 2087wꢀm, 1771w, 1682vs,
1555m, 1417mꢀs, 1379s, 1344s, 1298mꢀs, 1264m, 1198s, 1177mꢀs, 1093wꢀ
m, 1046mꢀs, 890m, 802mꢀs, 677wꢀm cm–1. 1H NMR (D2O): δ = 2.71 (s, 4H,
CH2, succinic anhydride); 2.58 (s, 4H, CH2, succinimide) ppm. 13C{1H}
10
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7

Dalton Transactions
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DOI: 10.1039/C7DT02702H
Figure 2. DFTꢀoptimized structures of possible intermediates involved in the oxidation of
L
ꢀprolinate to pyrrolidineꢀ2ꢀcarboxylate and relative
Gibbs energy values (kcal molꢀ1, T = 343.15 K). CꢀPCM/ωB97X calculations, water as continuous medium. Colour map: light grey, hydrogen;
dark grey, carbon; red, oxygen; blue, nitrogen; green, vanadium, light blue, spin density surface (isovalue = 0.01 a.u.). Cartesian coordinates of
the DFTꢀoptimized structures are collected in a separated. xyz file.
8

Page 9 of 10
Dalton Transactions
View Article Online
DOI: 10.1039/C7DT02702H
Figure 3. DFTꢀoptimized structures of possible intermediates in the interaction of glycinate with [V4O10(OH)2ꢁH2O]2ꢀ and relative Gibbs energy
values (kcal molꢀ1, T = 343.15 K). CꢀPCM/ωB97X calculations, water as continuous medium. Colour map: light grey, hydrogen; dark grey,
carbon; red, oxygen; blue, nitrogen; green, vanadium, light blue, spin density surface (isovalue = 0.01 a.u.). Cartesian coordinates of the DFTꢀ
optimized structures are collected in a separated .xyz file.
9

Dalton Transactions
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DOI: 10.1039/C7DT02702H
Graphical Abstract
Vanadium(V) Oxoanions in Basic Water Solution: a Simple Oxidative
System for the One Pot Selective Conversion of
2-Carboxylate
L-Proline to Pyrroline-
Lorenzo Biancalana, Giada Tuci, Fabio Piccinelli, Fabio Marchetti, Marco Bortoluzzi, and Guido
Pampaloni
The unusual, one pot conversion of LꢀProline to pyrrolineꢀ2ꢀcarboxylate, using simple V(V) species
(NH4VO3 or V2O5) as oxidants in basic water medium, is described. No reaction was observed with
primary and tertiary αꢀamino acids.