A comparative approach to the most sustainable protocol for the β-azidation of α,β-unsaturated ketones and acids

Article abstract of DOI:10.1039/c4gc01282h

In this contribution we have used green metrics analysis to compare the material efficiency, environmental impact, and safety-hazard impact in order to compare flow and batch procedures for azidation of α,β-unsaturated carbonyls. It has been proved that flow protocols possess a greener profile over the corresponding batch procedures based on identical chemistries. In this work the new flow procedure described is very efficient; however, the significant uncertainties in the environmental and safety-hazard impact scores are due to the lack of toxicity, hazard, and occupational exposure data available on trimethylsilyl azide and the resin catalysts used here. The results for the new flow procedure show significant and definite improvements over previously published work with respect to waste minimization/material efficiency and are consistent with satisfying green chemistry principles. The results obtained in this work prove the usefulness of our flow-approach for realizing highly efficient processes featuring minimal waste production.

Full text of DOI:10.1039/c4gc01282h

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ARTICLE TYPE
A comparative approach to the most sustainable protocol for the β-
azidation of α,β-unsaturated ketones and acids
a
b
b
John Andraos,* Eleonora Ballerini, and Luigi Vaccaro*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
In this contribution we have used our green metrics analysis to compare material efficiency,
environmental impact, and safety-hazard impact in order to compare flow and batch procedures for
azidation of α,β-unsaturated carbonyls. It has been proved that flow protocols possess a greener profile
over the corresponding batch procedures based on identical chemistries. In this work the new flow
procedure described is very efficient; however, the significant uncertainties in the environmental and
safety-hazard impact scores are due to the lack of available toxicity, hazard, and occupational exposure
data on trimethylsilyl azide and the resin catalysts used here. The results for the new flow procedure show
significant and definite improvements over previously published work with respect to waste
minimization/material efficiency and are consistent with satisfying green chemistry principles. The results
obtained in this work prove the usefulness of our flow-approach for realizing highly efficient processes
featuring a minimal waste production.
1
0
1
5
3
1
efficiency metrics alone have also been discussed. Examples of
life cycle analysis including environmental impact and
safety/hazard impact applied to organic reactions are still rare.
Introduction
3
2
In the last decade the importance of applying green metrics
analysis in upholding green chemistry principles has been
5
5
6
6
7
7
0
5
0
5
0
5
A key feature of metrics analysis that can help to gain further
acceptance by the wider chemistry community is the display of
results in an easy to understand graphical form that conveys
visually both the attributes and weaknesses of a given kind of
synthesis methodology, thereby guiding future optimization in a
directed manner. In this context the present work details the
application of material, environmental impact, and safety/hazard
impact metrics to azidation reactions of α,β-unsaturated carbonyl
1
2
2
3
3
4
4
0
5
0
5
0
5
recognized generally and specifically by the pharmaceutical
2
industry. Indeed, metrics analysis is central to the discipline of
green chemistry and is the defining feature of this emerging area
of chemistry. The use of metrics serves two important purposes:
it substantiates claims of greenness through rigorous quantitative
reasoning and it upholds ethical standards in the publication of
scientific literature with respect to the detailed disclosure of
experimental procedures for reproducible syntheses of
compounds. However, its application to organic synthesis
methodology has only been recently demonstrated in a few cases.
Most of these involve the application of material efficiency
33
derivatives using flow methodology. This new way of carrying
out organic transformations as opposed to the traditional glass
vessel is the chemist’s version of thinking outside the box.
Though this method has often been described as meeting green
principles such as improved safety through reduced contact with
hazardous reagents and the potential of recycling solvents rather
than their disposal after use, there has not yet been a metrics
comparison of this method applied to a given reaction with
previous literature procedures. This report also offers support for
these claims.
3
1c,e,4
metrics such as atom economy (AE), E-factor,
global
5
reaction mass efficiency (RME), and process mass intensity
6
7
(
PMI). Examples include synthesis of 1,3-oxazin-2-ones,
8
isoprene production, synthesis of PEG (polyethylene glycol)-
9
10
based supports, transition metal catalyzed reactions, pyrazole
1
1
syntheses,
three component synthesis of 1-amidoalkyl-2-
Our research has been recently focused on the optimization of
synthetic procedures employing eco-friendly reaction protocols
1
2
13
naphthols, glyphosate synthesis, phosgene and phosgene-free
1
4
syntheses of industrial chemicals,
oseltamivir phosphate
34
35
based on the use of water, solvent free conditions (SolFC) and
highly concentrated conditions (HiCC), combined with the use of
heterogeneous catalysts.
1
5
16
syntheses, (S)-3-aminobutanoic acid synthesis, rose oxide
1
7
18
synthesis, synthesis of metal salts of acetylacetonate, Biginelli
36
1
9
20
21
adducts, 1,3,4-thiadiazole-2-thiols, fine chemicals, ionic
In recent years, we have been interested in the use of organic
ammonium fluorides as way to activate Si-N and Si-O bonds. In
this field, we have reported two alternative protocols for the β-
azidation of α,β-unsaturated ketones based on the use of
commercially available Amberlite IRA900F as catalyst under
2
2
23
liquid syntheses,
sulfide oxidations,
photochemical
2
4
25
reactions, Elliott’s alcohol, synthesis of various methylating
2
6
27
agents,
pegylation of menadiol and podophyllotoxin,
2
8
29
bromination of olefins, elementary organic reactions, and Ro
3
0
24-5904 synthesis.
The limitations of applying material
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[journal], [year], [vol], 00–00 | 1

Green Chemistry
Page 2 of 11
3
5g
SolFC and on the use of PS-DABCOF
that was synthesized by our previously reported procedure. We
have also reported a protocol for the β-azidation of α,β- 60 fraction for the environmental impact (EI) and safety-hazard
2
as catalyst in water,
flow methodology described in this work unless otherwise noted.
3
4a
Uncertainty estimates based on a simple data set incompleteness
View Article Online
DOI: 10.1039/C4GC01282H
unsaturated carboxylic acids based on the use of PS-DABCOF as
impact (SHZI) scores were introduced as follows according to
equation (1) where, x is the number of missing parameters for all
substances used in a given reaction, n is the number of parameters
needed to estimate EI (n = 8) or SHZI (n = 11) for each
3
5a
5
0
5
0
5
catalyst under SolFC. β-azido-carbonyl compounds have been
-
synthesized by conjugate addition of N-nucleophile such as, N
to α,β-unsaturated carbonyl compounds. A number of target
3
molecules can be prepared via these intermediates, such as γ- 65 substance, and C is the total number of chemicals required in
amino alcohols and β-amino acids that are common motifs in
many natural and biologically active compounds.
According to the fact that our research goal is the definition of
efficient protocols with high levels of sustainability, we have also
been interested in the application of flow chemistry. In general,
flow reactors can be an efficient technology to reduce the
carrying out a given reaction including reagents, catalysts,
additives, ligands, reaction solvents, work-up materials, and
purification materials.
3
7
1
1
2
2
x
(
1)
%uncertain yt 
X 100
nC
environmental impact of synthetic processes. The use of flow 70 No weightings were attached to any of the parameters used since
methods offer the possibility of realizing synthetic processes in a
safe, reproducible and scalable manner; they may offer several
advantages as compared to traditional batch reactors such as the
minimization of waste and in particular of the amount of organic
such an approach is compounded by the problem of arbitrary
choice of weighting factors. Actual measures of uncertainty for
each parameter value are unknown since these are not reported in
the source references (e.g., error estimates for LD50 values are
3
8
solvent needed to isolate the final products and the optimization 75 not stated in any database compilation of such parameters). This
of the recovery and reuse of the solid catalysts.
In accordance with our previous reports in this field,
interested in the definition of generally useful and practical
procedures to recover and reuse the catalytic system and the
precludes any possibility of doing a thorough propagation of
errors statistical analysis. Though we acknowledge that our
approach is crude and simplistic we feel this interpretation of
uncertainty is good enough to flag EI or SHZI estimates that are
35c-e,36
we are
desired product with the minimal cost in terms of time and waste 80 calculated based on key missing data for specific compounds
disposal.
used in a given chemical transformation, and therefore to
interpret such estimates with appropriate caution. A complete
listing of chemicals and the associated raw data for determining
potentials is given in Table S1 in the Supporting Information.
Missing data are also indicated in that table. For each reaction,
radial polygons were used to display the results of all three
groups of metrics to gauge overall performance. The vector
magnitude ratio (VMR) obtained from the ratio of the vector
magnitude of the variables making up the radial polygon
diagrams versus those for the ideal green case as described
Methodology of Metrics Calculations
In carrying out a detailed green metrics analysis three groups of
metrics were examined: (a) material efficiency metrics (reaction
yield, AE, global RME, E-factor,
impact metrics (see Appendix for list of potentials, benign impact
index for waste materials ); and (c) safety-hazard metrics (see
Appendix for list of potentials, safety-hazard impact index for
8
9
9
5
0
5
3
5
1c-e
6
3
3
4
4
5
5
0
5
0
5
0
5
PMI ; (b) environmental
3
9
4
0
40
waste materials and for input materials ). To ensure fairness in
ranking, a set of reactions chosen for comparison leading to a
particular product had a common starting substrate. The only
variations were in the azide reagents and auxiliary materials such
as catalysts, reaction solvents, work-up materials, and purification
materials. All reactions examined were single-step reactions.
Most literature procedures disclosed auxiliary material
consumption, however, in cases when these were not disclosed
the following assumptions were made: volumes of each kind of
work-up extraction solvent was set equal to the volume of
reaction solvent (e.g., if ether, saturated sodium bicarbonate
solution, and brine were used in the work-up and 100 mL of
reaction solvent were used, then 100 mL of each wash solvent for
a total of 300 mL of work-up solvents was assumed), and the
mass of drying agent was set to 2 g if the volume of reaction
solvent was less than 20 mL or 10 g if the reaction volume was
between 100 mL and 500 mL. Undisclosed masses of silica gel
and volumes of eluents in chromatographic procedures could not
be estimated reliably; therefore PMI values for such procedures
appear as lower limits in the tables, i.e., values appear with a
41
previously was used as the overall measure of “greenness” for
ranking purposes. The trimethylsilyl azide reagent used in the
present work has been advertised as a safer azide transfer
42
reagent compared to hydrazoic acid and sodium azide, however
there has not been substantive evidence to support these claims as
would be required for the present green metrics analysis. For
example, this compound has no available data for the following
parameters: oral LD50, dermal LD50, occupational exposure
limit, water solubility, impact sensitivity, and Trauzl lead block
1
00 test for explosive power. However, there is only one anecdotal
report of an accidental explosion that has occurred with this
43
reagent. This shortcoming along with the uncertainties due to
missing parameters described above needs to be considered in the
interpretation of the ranking results for the present investigation.
1
05 Results and discussion
In this section we describe the results of the green metrics
analysis for the synthesis of the four β-azido products from their
respective α,β-unsaturated ketone or acid precursors.
“
greater than” inequality sign (>). Reactions with such
designations should be interpreted with caution as having an 110 (A) 4-azido-heptan-2-one
associated uncertainty with respect to rankings. Stoichiometric
amounts of water as reagent were used in the calculations for the
For the synthesis of this ketone, the green performances of
conventional batch and flow procedures may be directly
2
| Journal Name, [year], [vol], 00–00
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Page 3 of 11
Green Chemistry
compared. There were no other literature procedures available for
comparison (see Scheme 1).
the waste materials be composed of inherently lower impact
potentials with respect to environment and safety, but also that
View Article Online
5
0
the mass proportion of the most offending chemical with respect
DOI: 10.1039/C4GC01282H
Me
3 3
SiN
O
O
O
N
N
N
3
O
O
O
to the overall waste mass profile is kept to a minimum as far as
possible.
Amberlyst-F (cat.)
H
2
O
(Vaccaro - batch, 2006)
(Vaccaro - batch, 2012)
(Vaccaro - flow, 2012)
-
Me3SiOH
Me
3
SiN
3
(B) 3-azidocyclohexanone
3
PS-DABCOF
2
2
(cat.)
(cat.)
H
2
O
55 Scheme 2 shows the four known reactions for preparing 3-
4
4
45
azidocyclohexanone. The Xia 2003 and 2004 use sodium
azide as the azidation reagent, but only differ in the choice of
-
Me3SiOH
Me
3 3
SiN
3
46
PS-DABCOF
catalyst; whereas, the Miller and the present flow method use
2
H O
trimethylsilylazide in aqueous solution using DBU and
Amberlyst-F as catalysts, respectively. From Figure 4, the new
flow procedure has the lowest PMI overall. In the Miller plan, in
-
Me3SiOH
6
6
7
7
0
5
0
5
Me
3 3
SiN
O
N
3
O
Amberlyst-F (cat.)
H
2
O
(Vaccaro - flow, this work)
which was generated controlled stoichiometries of HN during
3
-
Me3SiOH
the reaction, the solvent usage is very large. These are
conservative estimate since the amounts of chromatographic
solvents were not disclosed; hence, the true E-factor and PMI
results for this method are much worse than present estimates
indicate. The new flow procedure has the highest VMR (see
Figures 5A and 5B and Table 3 and 4). From Figure 6, the
greatest environmental impact from waste material is ingestion
toxicity potential from trimethylsilanol (new flow procedure),
sodium azide (both Xia plans), and acetic acid (Miller plan). For
the safety-hazard impact from waste material, the skin dose
potential from trimethylsilanol (new flow procedure),
occupational exposure limit potential from sodium azide (both
Xia plans) and dichloromethane (Miller plan) are the main
contributors. For the safety-hazard impact from input material,
the corrosive liquid potential from cyclohexenone (new flow
procedure), OELP from sodium azide (both Xia plans) and
dichloromethane (Miller plan) are the main contributors.
5
Scheme 1 Literature plans to synthesize 4-azido-heptan-2-one from hept-
-en-2-one.
3
From Figure 1, the new flow procedure described in this work
lowers PMI by 59 % over the prior published flow procedure
and by 73% and 84 % over the batch procedures.
expected, the main contributor to E-factor and PMI for inputs is
solvent usage. The new flow procedure is not performed under
dry conditions and therefore the use of sodium sulfate is
eliminated (drying agent) in the work-up. Water is considered in
the calculation because it is consumed in a stoichiometric amount
according to the reaction mechanism. This reduction is consistent
with the highest VMR value found for the new flow procedure
3
4a
34a,35g
1
1
2
2
3
3
4
4
0
As
5
0
5
0
5
0
5
(
see Figures 2A and 2B and Tables 1 and 2). From Figure 3, the
major contributing potential to environmental impact from waste
generated for all three methods is ingestion toxicity potential:
trimethylsilanol (reaction byproduct) from both flow procedures
and ethyl acetate (work-up solvent) from the batch procedure.
The skin dose potential is the largest contributor to waste material
hazards coming from trimethylsilanol and ethyl acetate.
For the input materials, the main hazard potential in the new flow
procedure is risk phrase potential arising from trimethylsilyl
azide. Ethyl acetate contributes to skin dose and corrosive liquid
potentials. From Table 1, atom economies for all three methods
are identical since the balanced chemical equation is the same
(see Scheme 1). Reaction yield performances are virtually the
same over the three procedures. The least safety-hazard impact
score for input materials and the least environmental impact score
for waste materials are found for the new flow procedure. Though
the new flow procedure has the highest VMR values, it
apparently has the lowest values for benign index for waste
materials and for safety-hazard index for input materials
compared to the batch procedure which has the highest values for
these parameters. This apparent paradoxical situation arises since
both of these indexes are calculated based on mass weighted
impact potentials. In the case of the new flow procedure which
produces the least amount of waste in absolute terms (as
evidenced by its lowest PMI and E-factors), the proportion of the
waste coming from the most offending byproduct,
trimethylsilanol, is 63 %, whereas for the batch procedure it is
only 5 %. This example is an illustration of a key point in striving
for truly green syntheses. Optimization in the direction of
producing benign and safe waste products suggests that not only
8
0
Figure 1 PMI and E-factor profiles showing individual contributions for
the synthesis of 4-azido-heptan-2-one according to plans shown in
Scheme 1.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Green Chemistry
Page 4 of 11
View Article Online
DOI: 10.1039/C4GC01282H
Figure 2 Figure 2. (A) Radial polygons showing results of material and
environmental impact metrics; (B) Radial polygons showing results of
material, environmental impact, and safety-hazard metrics for the
synthesis of 4-azido-heptan-2-one according to plans shown in Scheme 1.
5
From Tables 3 and 4, we find that the Miller plan has the lowest
atom economy, both Xia plans have the highest EI scores due to
sodium azide reagent, and the new flow procedure has the lowest
EI and SHZI scores. The variation in waste benign index values is
small over the four synthesis methods - all are high. The new
flow procedure has a lower input safety-hazard index compared
to the Miller plan though the chemistry is very similar. The value
for the Miller plan needs to be interpreted with caution since its
SHI was determined with omission of the chromatographic
purification solvents ethyl acetate and hexane since the masses of
these were not disclosed. It is very likely that the new flow
procedure would score higher if the details of the Miller plan
were fully known. It is certain that these purification solvents will
account for the bulk of the total mass of input materials used for
the entire reaction.
1
1
2
0
5
0
Figure 3 (A) Waste environmental impact, (B) waste safety-hazard, and
(
C) input safety-hazard potential profiles showing percent contributions
Table 1 Summary of material and environmental impact metrics results
for the synthesis of 4-azido-heptan-2-one according to plans shown in
Scheme 1.
of potentials for the synthesis of 4-azido-heptan-2-one according to plans
shown in Scheme 1.
3
5
a
Plan
AE Yield PMI
BI
(waste)
VMR Total EI % U
For the safety-hazard impact of waste materials, the skin dose
potential from unreacted acrylic acid (new flow procedures),
occupational exposure limit potential from unreacted sodium
azide (Boyer and Blagg method) are the main contributors. For
the safety-hazard impact of input materials, the same profile
arises as for the safety-hazard impact of waste materials. There is
little variation in values of waste benign indexes - all are high.
in EI
%
%
score
Vaccaro
batch, 2006) 63.3
Vaccaro
batch, 2012) 63.3
Vaccaro
flow, 2012) 63.3
4
0
(
87
91
93
7.05 0.8243 0.6291 26.05 27.1
12.07 0.8040 0.6055 26.05 27.1
4.73 0.8199 0.6728 36.38 23.2
(
(
Vaccaro
(
flow,
O
Me3SiN3
HOAc
DBU (cat.)
O
this work)
% Uncertainty in total in total EI score
63.3
95
1.92 0.6243 0.7848 20.95 30.0
a
2
5
(Miller, 1999)
-
Me3SiOAc
N3
N3
Table 2 Summary of safety-hazard metrics results for the synthesis of 4-
O
O
NaN3
HOAc
PBu3 (cat.)
azido-heptan-2-one according to plans shown in Scheme 1.
a
(
Xia, 2003)
Plan
Input SHI
VMR
Total SHZI % U
score
in SHZI
- NaOAc
Vaccaro
batch, 2006)
Vaccaro
batch, 2012)
Vaccaro
O
O
O
O
NaN3
HOAc
Pyridine (cat.)
(
0.6167
0.5718
0.8349
0.5656
0.7268
0.7092
0.7755
0.8175
53.1
53.1
53.6
29.1
25.8
23.4
24.7
38.6
(
Xia, 2004)
(
N3
-
NaOAc
(flow, 2012)
Me3SiN3
Amberlyst-F (cat.)
H2O
Vaccaro
flow, this work)
Uncertainty in total in total EI score
(Vaccaro - flow, this work)
(
%
a
- Me3SiOH
N3
45
3
0
Scheme 2 Literature plans to synthesize 3-azidocyclohexanone from
cyclohexenone.
4
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Page 5 of 11
Green Chemistry
Table 3 Summary of material and environmental impact metrics results
for the synthesis of 3-azidocyclohexanone according to plans shown in
Scheme 2.
View Article Online
DOI: 10.1039/C4GC01282H
a
Plan
AE Yield PMI
BI
VMR Total EI % U .
in EI
%
%
(waste)
score
Vaccaro
(
this work) 60.7 98
Xia
3.2 0.9761 0.7572 290.1
20.8
16.7
8.3
(
2004)
Xia
62.9 95 25.2 0.9429 0.6277 4913.4
62.9 94 > 19.8 0.9267 0.6239 5025.5
51.3 90 > 59 0.9890 0.5987 558.0
(2003)
Miller
1999)
(
20.8
a
%
Uncertainty in total in total EI score
5
Table 4 Summary of safety-hazard metrics results for the synthesis of 3-
azidocyclohexanone according to plans shown in Scheme 2.
a
Plan
Input SHI
VMR
Total SHZI
score
% U
in SHZI
Vaccaro
this work)
Xia
(
0.7733
0.9343
0.9029
0.8747
0.8190
0.7628
0.7565
0.7391
89.8
22.7
15.2
10.6
19.7
(2004)
Xia
1389.1
1173.5
207.4
(2003)
Miller
1999)
(
a
%
Uncertainty in total in total EI score
2
0
Figure 6 (A) Waste environmental impact, (B) waste safety-hazard, and
(
C) input safety-hazard potential profiles showing percent contributions
of potentials for the synthesis of 3-azidocyclohexanone according to plans
shown in Scheme 2.
2
5
The input SHI value for the new flow procedure is apparently
lower than the other methods for the same reason as described for
the synthesis plans for 3-azidocyclohexanone
– the SHI
determinations for the other methods suffer from omission of
purification materials which were not disclosed.
3
0
O
O
NaN3
HOAc
O
O
(
Boyer, 1951)
HO
HO
HO
HO
N3
N3
-
NaOAc
NaN3
HOAc
(Blagg, 2006)
Figure 4 PMI and E-factor profiles showing individual contributions for
the synthesis of 3-azidocyclohexanone according to plans shown in
Scheme 2.
-
NaOAc
1
0
Me3SiN3
PS-DABCOF (cat.)
H2O
O
O
O
O
(
Vaccaro - flow, this work)
HO
HO
HO
HO
N3
N3
-
Me3SiOH
Me3SiN3
Amberlyst-F (cat.)
H2O
(
Vaccaro - flow, this work)
-
Me3SiOH
Scheme 3 Literature plans to synthesize 3-azidopropanoic acid from
acrylic acid.
Figure
5 (A) Radial polygons showing results of material and
3
5
1
5
environmental impact metrics; (B) Radial polygons showing results of
material, environmental impact, and safety-hazard metrics for the
synthesis of 3-azidocyclohexanone according to plans shown in Scheme
2
.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Green Chemistry
Page 6 of 11
Table 5 Summary of material and environmental impact metrics results
for the synthesis of 3-azidopropanoic acid according to plans shown in
Scheme 3.
View Article Online
DOI: 10.1039/C4GC01282H
a
Plan
AE Yield PMI
BI
(waste)
VMR Total EI % U
in EI
%
%
80
99
24
score
Vaccaro
Amb-F)
Vaccaro
PS-DABCOF) 56.1
(
56.1
4.5 0.9541 0.6978 3270.8 16.7
3.6 0.9955 0.7519 3270.8 16.7
> 39 0.9287 0.5349 7916.0 5.4
(
Boyer
(
1951)
58.4
58.4
4
8
Blagg
(
2006)
50 > 296 0.9910 0.5279 7797.9 3.6
a
%
Uncertainty in total in total EI score
5
Table 6 Summary of safety-hazard metrics results for the synthesis of 3-
azidopropanoic acid according to plans shown in Scheme 3.
Plan
Input SHI VMR Total SHZI
score
% U
in SHZI
Vaccaro
(
Amb-F)
0.8151
0.7878
0.8199
0.7101
0.7158
216.0
216.0
19.7
19.7
6.5
Vaccaro
PS-DABCOF) 0.8109
(
Boyer
(
1951)
Blagg
2006)
0.9058
0.9689
1315.2
1320.6
(
5.2
a
%
Uncertainty in total in total EI score
Figure 9 (A) Waste environmental impact, (B) waste safety-hazard, and
(C) input safety-hazard potential profiles showing percent contributions
of potentials for the synthesis of 3-azidopropanoic acid according to plans
shown in Scheme 3.
2
0
(
D) 4-azido-4-methyl-pentan-2-one
4
7
49
2
3
3
4
4
5
5
0
5
0
5
0
From Scheme 4, the Boyer and Davies plans employ sodium
azide in aqueous acetic acid to make 4-azido-4-methyl-pentan-2-
5
0
one, whereas, the Chung and Vaccaro plans use hydrazoic acid
and trimethylsilyl azide, respectively. Figure 10 shows that the
flow procedure has the lowest PMI and E-values. The Chung plan
has the highest solvent usage due to reaction solvents (chloroform
and hexane) and work-up solvents (dichloromethane) which
contributes to the high PMI and E-values. From Table 7, it also
has the lowest atom economy at 46 % compared with best plans
at 63 %. The Boyer plan has the lowest yield (38%) compared
with the flow procedure which has the highest (90%). The Boyer,
Davies, and Chung plans all have minimum estimates for PMI
due to the lack of disclosure of work-up and purification
materials. The flow procedure has lowest EI score and the lowest
SHZI score. The large EI scores for other plans arise from sodium
azide (INGTP, Boyer and Davies) and from hydrazoic acid
Figure 7 PMI and E-factor profiles showing individual contributions for
the synthesis of 3-azidopropanoic acid according to plans shown in
Scheme 3.
1
0
(
INGTP, Chung). For the environmental impact for waste
materials, the main contributions are skin dose potential from
trimethylsilanol (flow procedure), OELP from sodium azide
(
Boyer and Davies plans), and OELP from dichloromethane and
chloroform solvents (Chung plan) (see Figure 12). For the safety-
hazard impact for waste materials, the same results apply as for
the environmental impact for waste materials. For the safety-
hazard impact for input materials, the skin dose potential from
ethyl acetate and 4-methyl-pent-3-en-2-one (mesityl oxide) (flow
procedure), OELP from sodium azide (Boyer and Davies plans),
and OELP from dichloromethane and chloroform solvents
Figure
8 (A) Radial polygons showing results of material and
environmental impact metrics; (B) Radial polygons showing results of
material, environmental impact, and safety-hazard metrics for the
synthesis of 3-azidopropanoic acid according to plans shown in Scheme
1
5
(
Chung plan) are the main contributors. The waste BI for the new
3
.
flow procedure is noticeably lower than for the other plans – the
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 11
Green Chemistry
most offending chemical, trimethylsilanol byproduct, represents
6 % of total mass of waste. For the Boyer plan the most
2
3
0
Figure 10 PMI and E-factor profiles showing individual coVnietwribArutitciolenOsnfloinre
the synthesis of 4-azido-4-methyl-pentan-2-one 3 9t o/ C la
in Scheme 4.
offending unreacted sodium azide represents 5 % of the total
waste; whereas, for the Davies plan unreacted sodium azide is
only 0.9 % of the total waste. For the Chung plan unreacted
hydrazoic acid represents 0.2 % of the total waste. From Table 8,
the new flow procedure has the lowest SHI score: ethyl acetate
represents 20 % of input materials mass; mesityl oxide presents
D
a
O
c
I
c
:
o
1
r
0
d
.
i
1
n
0
g
4GC01282H
p ns shown
5
0
5
2
2 % of input materials mass; and trimethylsilyl azide which does
1
not have all its impact parameters known represents 39 % of
input materials mass. For the Boyer plan, sodium azide represents
6
of input mass. For the Chung plan, chloroform and
dichloromethane represent 10 % and 23 % of the total input mass,
respectively. No OELP data are known for hydrazoic acid which
accounts for 0.3 % of the input mass. From the radial polygons
shown in Figure 11 and the results in Tables 7 and 8, the new
flow procedure comes out on top with the highest VMR score.
% of the total input mass; whereas, for the Davies plan it is 1 %
1
O
NaN3
HOAc
O
N3
(Boyer, 1951)
-
NaOAc
3
5
Figure 11 (A) Radial polygons showing results of material and
environmental impact metrics; (B) Radial polygons showing results of
material, environmental impact, and safety-hazard metrics for the
synthesis of 4-azido-4-methyl-pentan-2-one according to plans shown in
Scheme 4.
O
NaN3
HOAc
O
N3
(
Davies, 1967)
-
NaOAc
HN3 + Et3Al
EtH
[Et AlN ]
-
O
O
2
3
N3
then 3H2O
(Chung, 1988)
-
-
2EtH
Al(OH)3
Me3SiN3
Amberlyst-F (cat.)
H2O
O
O
N3
(Vaccaro - flow, this work)
-
Me3SiOH
4
4
0
5
Scheme 4 Literature plans to synthesize 4-azido-4-methyl-pentan-2-one
Figure 12 (A) Waste environmental impact, (B) waste safety-hazard, and
2
0
from 4-methyl-pent-3-en-2-one (mesityl oxide).
(
C) input safety-hazard potential profiles showing percent contributions
of potentials for the synthesis of 4-azido-4-methyl-pentan-2-one
according to plans shown in Scheme 4.
Table 7 Summary of material and environmental impact metrics results
for the synthesis of 4-azido-4-methyl-pentan-2-one according to plans
shown in Scheme 4.
Plan
AE Yield PMI
BI
(waste)
VMR Total EI
score
% U
in EI
%
%
Vaccaro
(
this work) 61 90
Boyer
(
3.5 0.8921 0.7220
76.3
16.7
5.4
1951) 63.2 38 > 30.3 0.9493 0.5619 4721.5
Davies
1967) 63.2 66 > 137 0.9896 0.5657 4633.9
Chung
1988) 45.6 88 > 238 0.9975 0.5804 4074.8
% Uncertainty in total in total EI score
(
6.9
(
6.9
a
2
5
Table 8 Summary of safety-hazard metrics results for the synthesis of 4-
azido-4-methyl-pentan-2-one according to plans shown in Scheme 4.
Plan
Input SHI VMR
Total SHZI
score
% U
in SHZI
Vaccaro
this work)
Boyer
(
0.7697
0.9352
0.9697
0.9349
0.7972
0.7279
0.7349
0.7376
73.9
19.7
6.5
(
1951)
Davies
1967)
Chung
1988)
1173.2
1400.2
227.1
(
7.1
(
7.1
Experimental section
a
%
Uncertainty in total in total EI score
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Green Chemistry
Page 8 of 11
Unless otherwise stated, all solvents and reagents were used as 45 1 mm diameter solid glass beads, was charged on a glass column;
obtained from commercial sources without further purification.
GC analyses were performed by using Hewlett-Packard HP
the equipment was installed into a thermostated box and
View Article Online
connected, by using the appropriate valves, to a pump. The
DOI: 10.1039/C4GC01282H
5
890A equipped with a capillary column DB-35MS (30 m, 0.53
reaction mixture was continuously pumped (flow rate 1.0 ml/min)
through the catalyst column at 30 C for 6 h to reach the complete
°
5
mm), a FID detector and hydrogen as gas carrier. GC-EIMS
analyses were carried out by using a Hewlett-Packard HP 6890N 50 conversion to 3-azidocyclohexan-1-one. After this time the
Network GC system/5975 Mass Selective Detector equipped with
an electron impact ionizer at 70 eV. NMR spectra were recorded
air/solvent valve was opened and the pump was set to work at 5
-1
mL min in order to transfer the product into the reservoir and
empty the Amb-F column. To completely recover the product and
1
13
on a Bruker DRX-ADVANCE 400 MHz ( H at 400 MHz and
at 100.6 MHz) in CDCl using TMS as the internal standard.
Elemental Analyses were conducted on a Fisons EA1108CHN.
C
-1
1
0
3
clean the reactor, ethyl acetate (2 x 5 mL at a 1.5 mLmin , 0.1
55 mL/mmol of enone) was pumped from the air/solvent valve
through the catalyst column for 10 minutes (each fraction) and
then collected in the reservoir as well. The solvent was removed
(
88% of recovered solvent) under vacuum to furnish pure 3-
azidocyclohexan-1-one as an oil in 98% yield (13.622 g, 98
mmol). The catalyst was reused for three consecutive runs
without substantial loss of efficiency.
6
6
7
7
8
8
9
9
0
5
0
5
0
5
0
5
Flow experimental procedure for the β-azidation of 4-
methylpent-3-en-2-one with Amberlist-F as catalyst.
4-methylpent-3-en-2-one (100 mmol, 9.8 g) and TMSN3 (150
mmol, 19.91 mL) were charged into a glass column functioning
as a reservoir. Amberlyst-F (25 mol%, 6.316 g), suitably
dispersed in 1 mm diameter solid glass beads, was charged on a
glass column; the equipment was installed into a thermostated
box and connected, by using the appropriate valves, to a pump.
The reaction mixture was continuously pumped (flow rate 1.0
°
ml/min) through the catalyst column at 60 C for 3 h to reach the
Figure 13 General schematic representation of the flow reactor used.
complete conversion to 3-azidocyclohexan-1-one. After this time
the air/solvent valve was opened and the pump was set to work at
1
2
2
3
3
4
5
0
5
0
5
0
Thermostated chamber is not shown for clarity.
-1
5 mL min in order to transfer the product into the reservoir and
empty the Amb-F column. To completely recover the product and
Flow experimental procedure for the β-azidation of (3E)-
hept-3-en-2-one with Amberlist-F as catalyst.
-1
clean the reactor, ethyl acetate (2 x 5 mL at a 1.5 mLmin , 0.1
mL/mmol of enone) was pumped from the air/solvent valve
through the catalyst column for 10 minutes (each fraction) and
then collected in the reservoir as well. The solvent was removed
(
3E)-hept-3-en-2-one (100 mmol, 11.216 g) and TMSN (110
3
mmol, 14.6 mL) were charged into a glass column functioning as
a reservoir. Amberlyst-F (10 mol%, 2.632 g), suitably dispersed
in 1 mm diameter solid glass beads, was charged on a glass
column; the equipment was installed into a thermostated box and
connected, by using the appropriate valves, to a pump. The
reaction mixture was continuously pumped (flow rate 1.0 ml/min)
(
88% of recovered solvent) under vacuum to furnish pure 3-
azidocyclohexan-1-one as an oil in 90% yield (12.69 g, 90
mmol). The catalyst was reused for three consecutive runs
without substantial loss of efficiency.
°
through the catalyst column at 60 C for 2.5 h to reach the
complete conversion to 4-azidoheptan-2-one. After this time the
air/solvent valve was opened and the pump was set to work at 5
Flow experimental procedure for the β-azidation of acrylic
acid with Amberlist-F as catalyst.
Acrylic acid (100 mmol, 7.2 g) and TMSN (150 mmol, 19.91
3
-1
mL min in order to transfer the product into the reservoir and
empty the Amb-F column. To completely recover the product and
mL) were charged into a glass column functioning as a reservoir.
Amberlyst-F (25 mol%, 6.316 g), suitably dispersed in 1 mm
diameter solid glass beads, was charged on a glass column; the
equipment was installed into a thermostated box and connected,
by using the appropriate valves, to a pump. The reaction mixture
was continuously pumped (flow rate 1.0 ml/min) through the
-1
clean the reactor, ethyl acetate (2 x 5 mL at a 1.5 mLmin , 0.1
mL/mmol of enone) was pumped from the air/solvent valve
through the catalyst column for 10 minutes (each fraction) and
then collected in the reservoir as well. The solvent was removed
(88% of recovered solvent) under vacuum to furnish pure 4-
azidoheptan-2-one as an oil in 95% yield (14.725 g, 95 mmol).
The catalyst was reused for three consecutive runs without
substantial loss of efficiency.
°
catalyst column at 30 C for 3 h to reach the complete conversion
to 3-azidopropionic acid. After this time the air/solvent valve was
-1
opened and the pump was set to work at 5 mL min in order to
transfer the product into the reservoir and empty the Amb-F
column. To completely recover the product and clean the reactor,
Flow experimental procedure for the β-azidation of Cyclohex-
2
-enone with Amberlist-F as catalyst.
-1
1
00 ethyl acetate (2 x 5 mL at a 1.5 mLmin , 0.1 mL/mmol of acrylic
acid) was pumped from the air/solvent valve through the catalyst
column for 10 minutes (each fraction) and then collected in the
Cyclohex-2-enone (100 mmol, 9.6 g) and TMSN (150 mmol,
3
1
9.91 mL) were charged into a glass column functioning as a
reservoir. Amberlyst-F (25 mol%, 6.316 g), suitably dispersed in
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 9 of 11
Green Chemistry
reservoir as well. The solvent was removed (88% of recovered
solvent) under vacuum to furnish pure 3-azidopropionic acid in
0% yield (9.2 g, 80 mmol). The catalyst was reused for three
Appendix
List of Abbreviations
AE = atom economy
BI = benign index
EI = environmental impact
PMI = process mass intensity
RPHI = reaction pressure hazard index
RTHI = reaction temperature hazard index
SHI = safety-hazard impact
SHZI = safety-hazard index
VMR = vector magnitude ratio
6
6
0
5
View Article Online
DOI: 10.1039/C4GC01282H
8
consecutive runs without substantial loss of efficiency.
5
0
5
0
5
Flow experimental procedure for the β-azidation of acrylic
acid with PS-DABCOF as catalyst.
Acrylic acid (100 mmol, 7.2 g) was charged in a glass column
functioning as reservoir and TMSN (150 mmol, 19.91 mL) was
3
1
1
2
2
slowly added into it. PS-DABCOF (15 mol%, 5.4 g), suitably
dispersed in 1 mm diameter solid glass beads, was charged into a 70 Abbreviations for Environmental Impact Potentials (8 parameters):
AP = acidification-basification potential
second glass column. The equipment was installed into a
ODP = ozone depletion potential
thermostated box and connected, by using the appropriate valves,
SFP = smog formation potential
to a pump. The reaction mixture was continuously pumped (flow
rate 1.0 ml/min) through the catalyst column at 60 C for 0.5 h to 75 INHTP = inhalation toxicity potential
GWP = global warming potential
°
reach the complete conversion to 3-azidopropionic acid. After
this time the air/solvent valve was opened and the pump was set
INGTP = ingestion toxicity potential
BP = bioconcentration potential
ADP = abiotic resource depletion potential
Abbreviations for Safety-Hazard Potentials (11 parameters):
CGP = corrosive gas potential
CLP = corrosive liquid/solid potential
FP = flammability potential
OBP = oxygen balance potential
HGP = hydrogen gas generation potential
XVP = explosive vapour potential
XSP = explosive strength potential
ISP = impact sensitivity potential
OELP = occupational exposure limit potential
SDP = skin dose potential
-1
to work at 5 mL min in order to transfer the product into the
reservoir and empty the PS-DABCOF column. To completely
recover the product and clean the reactor, ethyl acetate (2 x 5 mL
8
8
9
0
5
0
-1
at a 1.5 mLmin , 0.1 mL/mmol of acrylic acid) was pumped from
the air/solvent valve through the catalyst column for 10 minutes
(
each fraction) and then collected in the reservoir as well. The
solvent was removed (90% of recovered solvent) under vacuum
to furnish pure 3-azidopropionic acid in >99% yield (11.4 g, 99.9
mmol). The catalyst was reused for three consecutive runs
without substantial loss of efficiency.
RPP = risk phrase potential
Conclusions
Acknowledgements
Based on the findings from this investigation, our green metrics
analysis covering material efficiency, environmental impact, and
safety-hazard impact corroborates that flow procedures for
azidation of α,β-unsaturated carbonyl substrates have a greener
profile over their published traditional batch procedures when
identical chemistries of reactions are compared. However, for the
analyses of a set of reactions to the same products by different
azide reagents and catalysts, these results need to be interpreted
with caution since some procedures did not disclose all auxiliary
material consumption. More importantly, the significant
uncertainties in the environmental and safety-hazard impact
scores for the new flow procedure described in this work are due
to the lack of available toxicity, hazard, and occupational
exposure data on trimethylsilyl azide and the resin catalysts used
This research has been developed and partially financed within
the National project “BIT3G“ – Italian Green Chemistry Cluster.
We gratefully acknowledge the Università degli Studi di Perugia,
and the Ministero dell’Istruzione, dell’Università e della Ricerca
3
3
4
4
5
5
0
5
0
5
0
5
9
5
(
MIUR) within the program “Firb-Futuro in Ricerca“ ref. N.
RBFR08JKHI for financial support. We also thank the
Fondazione Cassa di Risparmio di Terni e Narni“ for financial
support.
“
1
00 Notes and references
a
CareerChem, 504-1129 Don Mills Road, Don Mills, ON M3B 2W4
Canada, E-mail: c1000@careerchem.com
b
Laboratory of Green Synthetic Organic Chemistry, CEMIN –
Dipartimento di Chimica, Biologia e Biotecnologie, Università di
here. Despite these shortcomings, the present results for the new 105 Perugia Via Elce di Sotto, 8, 06123 Perugia, Italy; Fax: +39 075
flow procedure show significant and definite improvements over
past published work with respect to material efficiency and are
consistent with satisfying green chemistry principles. Waste
production has been significantly reduced by adopting our flow
conditions; in fact, the PMI has been considerably reduced for all
substrates. The flow protocol is characterized by the use of
minimal amounts of reagents and organic solvents during the
reaction and the workup and by an easy procedure for the
recovery and reuse of the catalyst. The results obtained in this
work prove the usefulness of our flow-approach for realizing
highly efficient processes featuring a minimal waste production.
We hope to test further the greenness of other flow procedures on
other chemical transformations to see if we find similar
advantages over conventional batch processes.
5855560; Tel: +39 075 5855541; e-mail: luigi.vaccaro@unipg.it
†
Electronic Supplementary Information (ESI) available: materials data.
See DOI: 10.1039/b000000x/
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