Selective Synthesis in Microdroplets of 2-Phenyl-2,3-dihydrophthalazine-1,4-dione from Phenyl Hydrazine with Phthalic Anhydride or Phthalic Acid

Article abstract of DOI:10.1002/chem.201805585

Pyridazine derivatives are privileged structures because of their potential biological and optical properties. Traditional synthetic methods usually require acid or base as a catalyst under reflux conditions with reaction times ranging from hours to a few days or require microwave assistance to induce the reaction. Herein, this work presents the accelerated synthesis of a pyridazine derivative, 2-phenyl-2,3-dihydrophthalazine-1,4-dione (PDHP), in electrosprayed microdroplets containing an equimolar mixture of phenyl hydrazine and phthalic anhydride or phthalic acid. This reaction occurred on the submillisecond timescale with good yield (over 90 % with the choice of solvent) without using an external catalyst at room temperature. In sharp contrast to the bulk reaction of obtaining a mixture of two products, the reaction in confined microdroplets yields only the important six-membered heterocyclic product PDHP. Results indicated that surface reactions in microdroplets with low pH values cause selectivity, acceleration, and high yields.

Full text of DOI:10.1002/chem.201805585

A Journal of
Accepted Article
Title: Selective synthesis in microdroplets of 2-phenyl-2,3-
dihydrophthalazine-1,4-dione from phenyl hydrazine with phthalic
anhydride or phthalic acid
Authors: Richard Neil Zare, Dan Gao, Feng Jin, and Xin Yan
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201805585
Link to VoR: http://dx.doi.org/10.1002/chem.201805585
Supported by

10.1002/chem.201805585
Chemistry - A European Journal
COMMUNICATION
Selective synthesis in microdroplets of 2-phenyl-2,3-
dihydrophthalazine-1,4-dione from phenyl hydrazine with phthalic
anhydride or phthalic acid
Dan Gao,†[a, b] Feng Jin,†[a] Xin Yan,[a] and Richard N Zare*[a]
Dedication ((optional))
Abstract: Pyridazine derivatives are privileged structures because of
their potential biological and optical properties. Traditional synthesis
methods usually require acid or base as a catalyst under reflux
conditions with reaction times ranging from hours to a few days or
require microwave assistance to induce the reaction. Herein, we
present the accelerated synthesis of a pyridazine derivative, 2-phenyl-
concentrated H2SO4, HCl/H2O, ice acetate acid) as catalysts. It is
well noted that although microwave-assisted methods can be
applied for these reactions, the same isomers as that of bulk
reactions were obtained without using catalysts.[11] Only when
additional acid or base is used as a catalyst in the microwave-
assisted reaction could the single six-membered heterocyclic
product be generated.[12]
2,3-dihydrophthalazine-1,4-dione,
PDHP,
in
electrosprayed
microdroplets containing an equimolar mixture of phenyl hydrazine
and phthalic anhydride or phthalic acid. This reaction occurred on the
submillisecond timescale with good yield (over 90% with the choice of
solvent) without using an external catalyst at room temperature. In
sharp contrast to the bulk reaction of obtaining a mixture of two
products, the reaction in confined microdroplets yield only the
important six-membered heterocyclic product PDHP. Results
indicated that surface reactions in microdroplets with low pH values
cause selectivity, acceleration, and high yield.
Recently, micron-sized microdroplets have been shown as a
unique platform to investigate reaction products, mechanisms,
and kinetics.[13] Chemical reactions in microdroplets exhibit
specific properties that are not observed in bulk solutions,
especially dramatic acceleration of reaction rates, which are often
thousands to millions of times greater than that in the bulk.[14]
Instead of showing remarkable reaction rate acceleration, some
reactions in microdroplets show completely different reaction
routes, possibly owing to the significantly different
microenvironment in microdroplets. For example, our research
group found that the Diels–Alder reaction of 3,5-hexadienyl
acrylate ester in microdroplets could not obtain the desired Diels–
Alder product in all cases even in the presence of catalyst, but just
generated instead the hydrolyzed product, hexa-3,5-dien-1-ol.[15]
In contrast, the desired Diels-Alder product can be easily obtained
in aqueous media at high temperature using indium (Ⅲ) triflate as
a catalyst in bulk-phase.[16] In this work, we present the selective
and high-yield synthesis of an important pyridazine derivative, 2-
phenyl-2,3-dihydrophthalazine-1,4-dione, from phenyl hydrazine
and phthalic anhydride or phthalic acid in microdroplets without a
catalyst on the submillisecond timescale at room temperature and
atmospheric pressure. In sharp contrast to bulk reaction, the
reaction of phenyl hydrazine and phthalic anhydride in
microdroplets not only caused dramatic acceleration but also
showed excellent selectivity to the target six-membered
heterocyclic product. For the reaction of phenyl hydrazine and
phthalic acid, it shows a striking reaction route in microdroplets
without using a catalyst to give the target product that cannot
occur under bulk conditions. Some insights how these reactions
occur in microdroplets are also put forward.
Pyridazine derivatives, a fascinating class of six-membered
heterocyclic compounds with two adjacent nitrogen atoms, have
been found to possess many biological properties, such as anti-
inflammatory,[1] antibacterial,[2] anticancer,[3] cardiovascular
diseases,[4] and agrochemical activities.[5] Owing to their biological
importance, these chemicals are favored by both synthetic and
medicinal chemists, among which, an important six-membered
pyridazine derivative, 2-phenyl-2,3-dihydrophthalazine-1,4-dione,
was reported to have very significant biological activities against
osteosarcoma,[6] glioma,[3] hypolipidemic,[7] and bacterials.[8] In
addition, 2-phenyl-2,3-dihydrophthalazine-1,4-dione can be used
as important optical intermediates.[9] Traditional methods for
synthesizing these pyridazine derivatives require acid or base
catalysts, and the reactions need to be performed under solvent
reflux from hours to days at high temperature to obtain high yields
of products.[10] Furthermore, in most cases, five-membered
heterocyclic isomer byproduct was simultaneously obtained, and
it can be transformed to the desired six-membered product under
the condition of base (typically ethanolic sodium) or acid (such as
As shown in Figure 1, we used two experimental setups to
perform the microdroplets reactions. One is the direct spray of the
microdroplets into the inlet of a mass spectrometer for real-time
analysis of the reaction. Another is the offline collection of the
microdroplets for further structural identification. In both cases the
microdroplets were generated by nebulization of a solution
containing phenyl hydrazine 1 (10 µM) and phthalic anhydride 2
(10 µM) in organic solvent with a high pressure nebulizing gas (N2,
120 psi). We apply a positive voltage to the spray source for online
spraying. If instead we apply a negative voltage to the spray
source, no products are observed. For offline collection, no
voltage has been applied. Many reports have shown that the sizes
[a] Dr. D. Gao,[ †] Dr. F. Jin, [ †] Dr. Y. Xin, Prof. R. N. Zare
Department of Chemistry
Stanford University
333 Campus Drive, Stanford, CA 94305-5080 (USA)
E-mail: zare@stanford.edu
[b] Dr. D. Gao
State Key Laboratory of Chemical Oncogenomics,
the Graduate School at Shenzhen, Tsinghua University
Tsinghua Campus, The University Town, Shenzhen, 518055, China
[†] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201805585
Chemistry - A European Journal
COMMUNICATION
(A) Microdroplets
ACN/H O (9:1; V/V) as solvent
(B) 30 min bulk reaction
ACN/H O (9:1; V/V) as solvent
(A)
N2 sheath gas
2
2
+
+
[3+H]+
239.0810
[1+H]
[4+Na]
279.0724
Reaction distance
109.0756
100
50
0
1.0
0.5
0
ESI source
1.0
N2
N2
MS inlet
+
[4+H]
257.0908
239.1251
0.5
Reactant
solution
239.02 239.06 239.10 239.14
m/z
[3+Na]+
261.0630
+
[1+H]
109.0753
+
[4+2Na-H]+
[4+2Na-H]
301.0543
HV
+
-
157.0832
150
245.0779
250
301.0554
0
100
100
200
m/z
300
150
200
m/z
250
300
(B)
Reactant
solution
O
(C)
microdroplets
NHNH2
NH
N
O
bulk, acetic acid
reflux,125 ºC, 4 h
O
+
N2 sheath gas
O
3
O
COOH
H
N
1
2
bulk
r.t.
N
H
O
4
Figure 2. Mass spectra of the reaction at room temperature of phenyl hydrazine
1 with phthalic anhydride 2 in (A) microdroplets and (B) bulk-phase without
catalyst and without refluxing. (C) The microdroplet reaction led to significant
product 3 formation with a small amount of product 4, whereas the bulk-phase
reaction of 1 and 2 with acetic acid as catalyst and reflux at high temperature
led to product 3, but without catalyst at room temperature only form product 4.
glass tube
Reaction distance
Figure 1. Schematic diagrams of the experimental setups used in our study for
the reaction study of phenyl hydrazine with phthalic anhydride in microdroplets.
Extent of reaction depends on the distance between the ESI tip and MS inlet for
direct spray or between the ESI tip and the collection surface for offline spray.
(A) Directly electrospray a solution containing two reactants to the MS inlet. A
+5 kV of voltage was applied to the syringe needle. (B) Offline collection of the
microdroplet using a glass vial with a syringe pinhole on the cap. No voltage
was applied.
distance provides more time for reaction and also allows more
microdroplets evaporation which further concentrates the
reagents.[19] We varied the distance between the spray source
and the MS inlet from 1 cm to 7 cm, corresponding to approximate
flight times of 50 µs to 350 µs. ACN/water (9/1, v/v) was used as
the solvent for the online spray of microdroplets. As shown in
Figure 3A, the conversion ratio of product 3 increased gradually
from 10% to 30% as the distance increased from 1 cm to 7 cm,
as determined from the intensity of product 3 relative to the sum
of intensities of product 3 and reagent 1, assuming the same
ionization efficiency.
However, the conversion ratio of product 3 is a little low. We
find that the choice of solvent greatly influences the reaction
conversion. We investigated the use of ACN, dimethylformamide
(DMF), DMF/ACN (1:1; v/v), and different volume ratios of DMF
to water. Because DMF is low volatile, and has strong ion
suppression so that it is not recommended for ESI-MS. Therefore,
we used the offline spray setup without applying external voltage
to collect the microdroplets and subsequently anayzed the
collected droplets by ESI-MS after redissolving in ACN/water (9:1;
v/v) to avoid the strong ion suppression of DMF. The reaction
efficiency in microdroplets is found to be closely related to multiple
properties of the microdroplet, such as evaporation, charge
accumulation, droplet lifetime, solubility, polarity of the droplet,
and so on. We observed that the maximum reaction progress in
the microdroplets (about 90% yield of product 3) is achieved using
DMF as the solvent (Figure 3B). DMF, with moderate high
dielectric coefficient and solubilizing power is an obviously
beneficial solvent for stabilizing the low pH environment, and
dissolving hydrophobic compounds. In addition, due to its very
low volatility (a vapor pressure of 2.7 at 20 ºC), the average
droplet lifetime can be kept longer to confine the reagent in highly
charged microdroplets which helps to improve the reaction
efficiency.
of microdroplets under these conditions range from 1 to 50 µm.
The travelling distance of the microdroplets at atmospheric
pressure was constant (3 cm) before the microdroplets enter the
mass spectrometer and the reaction stops. We estimate the
reaction time to be ~ 300 µs on the basis of the droplet speed (~80
m/s).[17] The reaction products were measured by ESI-MS in
positive ion mode. As shown in Figure 2A, the main product 3, 2-
phenyl-2,3-dihydrophthalazine-1,4-dione, and a small amount of
product 4 were observed in the microdroplets generated by the
above two strategies. To determine the structures of product 3
and 4, we performed tandem mass spectrometry using collision-
induced dissociation (CID) (See Figure S1 in Supporting
Information). In sharp contrast to the behavior in microdroplets, in
bulk only the open ring product 4 and residual reagent 1 were
detected when reacted for 30 min in ACN/water (9/1, v/v) (Figure
2B). Many studies have demonstrated that in order to obtain the
product 3, acid or base should be used as a catalyst and the
solution should be refluxed at high temperature.[10, 18]
We further performed bulk-phase reactions in acetic acid with
reflux condition to compare with that reactions in microdroplets.
The product are analyzed by NMR and high-resolution mass
spectrometry. The results showed that the six-membered
heterocyclic product 3 was generated, which is in accordance with
the data in microdroplets (Figure S2 in Supporting Information).
Figure 2C shows the reaction between 1 and 2 at room
temperature in microdroplets without using catalysts and in bulk-
phase with and without catalysts.
The distance between the electrospray source and the MS inlet
greatly influences the reaction conversion ratio. An increase in
On the contrary, when a DMF-water mixture was used as the
solvent, the conversion ratio of product 3 decreased with the
decreasing amount of DMF. Water is a high dielectric coefficient
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10.1002/chem.201805585
Chemistry - A European Journal
COMMUNICATION
(A)
(B)
2 toward reagent 1, forming the common intermediate 4. As
reported by Rai’s research group, a similar intermediate could be
formed at near neutral pH condition.[21] Then, under the condition
of low pH in microdroplets (not in bulk reaction), the intermediate
4 undergoes intramolecular nucleophilic attack to give the six-
membered product 3. This is the rate-limiting step with a high
threshold, so it is obvious that this reaction overcomes the high
energy barrier through proton catalysis on the microdroplet
surface. Traditional bulk reactions of phenyl hydrazine and
phthalic anhydride without using acid or base catalysis form the
five-membered heterocyclic product 2-(phenylamino)isoindoline-
1,3-dione along with 3. The same is true of microwave-assisted
synthesis methods. However, only the six-membered heterocyclic
product 3 was formed in microdroplets. It is noted that both NH
groups can be treated as nucleophilic sites, but NH in red color
with number 1 is close to the electronic-withdrawing group C=O,
which will lead to a weaker nucleophilic ability than the other NH
in purple with number 2. Therefore, the NH group in purple will be
easier to attack the carbonyl to form the six-memberd product 3.
Furthermore, the five-membered product was reported to be able
to transform into the six-membered product with acid as a catalyst.
The low pH enviroment offered by microdroplets may also
increase the efficiency to transform the five-membered product
quickly into the six-membered product 3. Thus, this is might be
the reason why only the six-membered product 3 was observed
in the microdroplet reaction without a catalyst.
100
80
60
40
20
0
ACN/H2O (9:1; V/V) as solvent
30
25
20
15
10
5
0
1
1
1
4
/
1
F
M
1
2
3
4
5
6
7
N
/
1
/
4
/
1
C
A
,
N
,
,
,
Distance (cm)
D
O
O
O
2
2
H
C
2
H
A
/
/
H
/
/
F
M
F
M
F
M
F
M
D
D
D
D
Figure 3. (A) Conversion ratio of product 3 in microdroplets by direct spraying
the solution containing reactants 1 and 2 into the ESI source where the ESI tip
was moved from 1 cm to 7 cm. (B) The effects of different solvents on the
conversion ratio of product 3 in microdroplets generated by offline spraying the
reaction solution. The distance between the ESI tip and the glass vial was kept
at 3 cm.
proton solvent, but its low solubility for common organic
substances may limit the yield. Moreover, when DMF/ACN (1:1;
v/v) was used as the solvent, a roughly similar conversion ratio of
product 3 was observed when compared with that using DMF
alone. The possible reason might be benefit from the comparable
stability of microdroplet lifetime with similar surface-charge
accumulation on the droplet surface and solubility toward
reagents, intermediate, and products between DMF and
DMF/ACN (1:1; v/v) as solvent. The efficiency of product
formation in ACN microdroplet is a bit low, about 20% of
conversion ratio. This behavior might be explained by high
volatility (a vapor pressure of 72.8 torr at 20 ºC) which results in
short-lived droplets, causing insufficient time for the reaction to
occur to a greater extent. From the above results, DMF can be
used as the optimum solvent for the microdroplet reaction and
was used in the following experiments.
Because the microdroplets were generated through online
spray with a positive voltage applied on the spray source and
offline spray without voltage, we further investigated whether
voltage altered the reaction. As shown in Figure S3, Supporting
Information, voltage had nearly no effect on the conversion ratio
of product 3. From the online and offline spray results, we also
conclude that the reaction in microdroplets is markedly
accelerated when comparing to the bulk reaction, which takes
hours to days. The acceleration of this reaction rate can be
attributed to abundant positive charges in confined aqueous
microdroplets, which has been demonstrated by Prof. Voth
previously.[20] This leads to high acidity, which helps to make the
reaction happen. This behavior is consistent with previous reports
that acid can promote the reaction.
To further understand the possible mechanism of the
microdroplet reaction, we investigated the reaction progress using
DMF as the solvent with different reaction times by changing the
offline spray distance between the spray tip and the glass vial. As
shown in Figures 4A-C, as the distance increased, the product 3
ion intensity increased while the product 4 ion intensity decreased.
When the distance was 1 cm, 4 cm, and 7 cm, the conversion
ratio of product 3 was 67%, 86%, 98%, respectively. Figure 4D
shows the ratio of product 4 to product 3 with increasing offline
spray distance. We interpret this behavior to indicate that product
4 is an intermediate of this reaction, which is converted in the
microdroplet environment to 3. The sharp differences between
bulk-phase and microdroplets reactions might be due to
significantly different reaction routes caused by distinctly different
reaction environments. We suggest the possible reaction
mechanism shown in Figure 4E. In the first step, both bulk
reaction and microdroplets undergo nucleophilic attack of reagent
We further investigated the relationship between the
reactants‘ concentration and conversion ratio of product 3 using
the offline spray setup with the distance fixed at 3 cm. We found
that when the reactant concentrations increased from 10 µM to
100 mM, the conversion ratio of product 3 decreased from 76.0%
to 18.4% (see Table S1, Supporting Information). Recently
reported data in our group showed that the chemicals were fully
261.0635 [3+Na]+
1.0 Distance: 7 cm
(A)
(C)
(E)
Distance: 1 cm 261.0623 [3+Na]+
(B)
1.0
[4+Na]+
279.0728
0.5
0.5
[3+H]+
245.0773
[4+H]+
257.0908
[4+Na]+
279.0742
262.0670
239.0817
[3+H]+
239.0804
273.8702
270 280
250.1766
250
277.0375
245.0785 256.1082
240 250 260
0
0
240
260
m/z
270
280
m/z
(D)
261.0635 [3+Na]+
Distance: 5 cm
1.0
60
40
20
0
0.5
0
[4+Na]+
279.0742
277.0375
[3+H]+
239.0817
0
1
3
5
7
240
250
260
m/z
270
280
Distance (cm)
H
NH
H
O
H
O
NH
H
O
N
N
H
N
N
bulk-phase
r.t.
O
+
O
H
OH
O
O
O
2
4
1
ESI,microdroplets
r.t.
H+
O
O
H
OH
H
H
N
N
2
N N
NH
-H2O
1
microdroplets
N
OH
OH
OH
[
4+H]+
OH
OH
rate-limiting step, high threshold
Figure 4. (A-C) Mass spectra of the microdroplets generated by offline spray
with the reaction distance varied from 1 cm to 7 cm. (D) Ratio of product 4 to
product 3 with respect to distance increased from 1 cm to 7 cm. (E) The possible
mechanism for the reaction of phenyl hydrazine 1 and phthalic anhydride 2 in
microdroplets.
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COMMUNICATION
O
O
O
O
NHNH
2
a reaction time of about 350 µs. In sharp contrast to bulk reactions,
(A)
OH
OH
NH
N
the microdroplet reactions occurred on
a submillisecond
+
timescale, indicating a remarkable acceleration of the reaction
rate. Moreover, this reaction in microdroplets shows excellent
selectivity yielding only the important six-membered heterocyclic
product 3. This behavior indicates an extremely different reaction
pathway in the confined microdroplets. We suggest that the
enhancement of the reaction rate and selectivity may be attributed
to a surface reaction in the confined microdroplets having low pH
values, which is enhanced by the positive charging of the
microdroplets.
[3+Na]+
261.0635
(B)
1.0
0.5
266.1727
250.1778
182.1903
Experimental Section
299.1103
300 350
0
Online analysis of electrospray microdroplets: The aqueous
solution of phthalic anhydride and phenyl hydrazine was injected
at the flow rate of 5 µL/min by a menchanical pump through a
syringe to the fused-silica capillary directing toward a mass
spectrometer inlet. A coaxial sheath gas ( N2 at 120 psi) flow
around the capillary results in nebulization to help the formation
of microdroplets. The distance between the spray source and the
mass spectrometer inlet was varied from 1 to 7 cm to monitor the
progress of reaction. A voltage of +5 kV of was applied to the
syringe needle. The temperature of the heated capillary inlet was
maintained at approximately 275 ºC and capillary voltage at 44 V.
To confirm the structures of reactants, intermediates, and
products, tandem mass spectrometry was conducted by collision
induced dissociation (CID). Mass spectra were all detected by a
high-resolution Orbitrap mass spectrometer (LTQ Orbitrap XL
Hybrid Ion Trap-Orbitrap; Thermo Scientific).
Offline collection of electrospray microdroplets: For the offline
collection setup, no voltage was applied to the syringe, and the
generated microdroplets were collected using a glass vial with a
cap on the top for further mass spectrometry (MS) detection.
Exhaust gas was pumped out from a syringe pinhole of the cap,
avoiding loss of products. The spray distance between the outlet
of the spray tip and bottom of the vial was varied from 1 to 7 cm
to investigate its influence on the reaction yield. Upon completion
of the reaction, the structures of the collected products were
measured using mass spectrometry.
100
150
200
250
m/z
Figure 5. (A) Phenyl hydrazine reacted with phthalic acid to form product 3 in
microdroplets. (B) Mass spectrum of the microdroplets generated by offline
spraying the mixture of phenyl hydrazine and phthalic acid.
occupied on the surface of the microdroplet when the
concentration was 10 µM.[23] Therefore, this phenomenon might
be explained by surface saturation. This explanation seems
sensible if we assume that the major part of the reaction takes
place at or near the microdroplet surface.
It is worth mentioning that when we electrosprayed a standard
solution of phthalic anhydride to the mass spectrometer, its own
hydrogen or sodium adducts in the positive ion mode or
deprotonated product in the negative ion mode cannot be
detected. As shown in the mass spectra (see Figure S4A-S4D,
intense ion signals at m/z 165.0914 and m/z 179.0350 were
observed in negative ion mode when methanol was used as
solvent, whereas only the main ion signal at m/z 165.0914 were
observed when ACN was used as solvent. We speculate that m/z
165.0914 and m/z 179.0350 were phthalic acid and 2-
(methoxycarbonyl)benzoic acid separately according to their
tandem mass spectra. The results indicated that in microdroplets
phthalic anhydride also underwent chemical reaction with methyl-
containing solvent and water (See Figure S4E). However,
previous researches have demonstrated that the hydrolysis of
phthalic anhydride should be catalyzed by buffer bases.[22]
Compared with the reaction in bulk condition, the hydrolysis of
phthalic anhydride in microdroplets showed significantly different
behavior.
Bulk-phase reactions: Bulk-phase reactions at two different
conditions were carried out to compare with that occurring in the
microdroplets. One reaction was performed at room temperature
without using a catalyst for 30 min, and another was using acetic
acid as the catalyst and reflux at 125 ºC for 4 h. The
concentrations of both reactants were 10 mM.
Inspired by this result, we investigated the microdroplet reaction
of phenyl hydrazine and phthalic acid using the offline spray setup.
As expected, a strong ion signal of product 3 and a very low ion
signal of intermediate 4 were observed (see Figure 5). Note that
there appears to be no previous report of the reaction of phenyl
hydrazine with phthalic acid to yield product 3, although Iqbal and
co-workers do find that derivatives of phthalic acid and phenyl
hydrazine react but under harsh conditions.[24] This results
indicated that reaction of phenyl hydrazine and phthalic acid
Acknowledgments
This work was supported by the Air Force Office of Scientific
Research through a Basic Research Initiative grant (AFOSR
FA9550-16-1-0113) and the National Natural Science Foundation
of China (No. 21675096).
undergoes
a
distinctly different reaction route between
microdroplets and bulk-phase. Once again, the formation of
product 3 in microdroplets might be attributed to the accumulation
of catalytic protons near the droplet surfaces.
Keywords: liquid microdroplets • pyridazine • selective
synthesis • reaction acceleration • mass spectrometry
In summary, we have synthesized product 3 by the reaction of
phenyl hydrazine with phthalic anhydride or phthalic acid via
intermediate 4 in microdroplets at room temperature with high
yields without using additional acid or base catalysts. DMF was
demonstrated to be the best solvent for this microdroplet reaction,
with a yield of product 3 up to 98% when the distance between
the spray tip to the glass vial extended to 7 cm, corresponding to
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Chemistry - A European Journal
COMMUNICATION
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This article is protected by copyright. All rights reserved.

10.1002/chem.201805585
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
O
We present the accelerated synthesis
of a pyridazine derivative, 2-phenyl-
2,3-dihydrophthalazine-1,4-dione, in
electrosprayed microdroplets
containing a room-temperature
mixture of phenyl hydrazine and
phthalic anhydride or phthalic acid
without using catalysts.
Dan Gao†, Feng Jin†, Xin Yan, Richard N
Zare*
O
O
O
NHNH2
O
without catalysts
microdroplets
NH
N
+
or
O
O
Page 1 – Page 4
OH
OH
Selective synthesis in microdroplets
of 2-phenyl-2,3-dihydrophthalazine-
1,4-dione from phenyl hydrazine with
phthalic anhydride or phthalic acid
261.0635
1.0
0.5
0
Microdroplets
301.0562
159.0529
128.9534
279.0742
239.0817
100
150
200
m/z
250
300
This article is protected by copyright. All rights reserved.