Pyridazinones from Maleic Hydrazide: A New Substrate for · 2020-02-25 · 2H-pyridazin-2-one (maleic hydrazide) tautomers (1,2-dihydropyridazine-3,6-dione not shown); (c) combined

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Pyridazinones from Maleic Hydrazide: A New Substrate for the Mitsunobu Reaction

Journal: Canadian Journal of Chemistry

Manuscript ID cjc-2019-0474.R1

Manuscript Type: Article

Date Submitted by the Author: 15-Jan-2020

Complete List of Authors: Rodriguez, Christina; Wilfrid Laurier University, Department of Chemistry and BiochemistryKiriakopoulos, Rachel; Wilfrid Laurier University, Department of Chemistry and BiochemistryHiscock, Lana; Wilfrid Laurier University, Department of Chemistry and BiochemistrySchroeder, Zachary; Wilfrid Laurier University, Department of Chemistry and BiochemistryDawe, Louise; Wilfrid Laurier University, Department of Chemistry and Biochemistry

Is the invited manuscript for consideration in a Special

Issue?:J Wuest

Keyword: Crystal engineering, Mitsunobu reaction, pyridazinones, pyridazinols, Cambridge Structural Database analysis

https://mc06.manuscriptcentral.com/cjc-pubs

Canadian Journal of Chemistry

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Pyridazinones from Maleic Hydrazide: A New Substrate for the Mitsunobu Reaction

Christina Rodriguez†, Rachel Kiriakopoulos†, Lana K. Hiscock, Zachary Schroeder, Louise N. Dawe*

†Co-authors contributed equally to this work.

Department of Chemistry and Biochemistry, Wilfrid Laurier University, 75 University Ave. W., Waterloo, ON, N2L 3C5, Canada

*[email protected] ORCID: 0000-0003-3630-990X

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mailto:[email protected]

http://orcid.org/0000-0003-3630-990X

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Abstract

Crystal engineered organic frameworks assembled using hydrogen bonding are known, and

examples constructed from hydroxypyridine/pyridone as the dominant source of hydrogen

bonding have been reported. Less explored, are analogous systems based on maleic hydrazide.

Herein, a two-step route (Mitsunobu followed by Schiff base reactions) to asymmetrically

substituted pyridazinones from maleic hydrazide (step 1) is reported with 2-, 3-, or 4-

pyridinecarboxaldehyde (step 2). Upon reaction with 4-pyridinecarboxaldehyde, single crystals

suitable for analysis via X-ray diffraction were obtained. Careful examination of this solid state

structure, and comparison with a large number of related structures in the Cambridge Structural

Database, revealed a pyridazinone (vs. pyridazinol) core and persistent “head-to-tail” 𝑅22(8)

hydrogen bonded dimers. While these pyridazinones were originally considered suitable for use

as ligands for metal cation coordination, challenges in achieving this outcome were encountered.

Graphical Abstract

Keywords

Crystal engineering, Mitsunobu reaction, pyridazinones, pyridazinols, Cambridge Structural

Database analysis

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Introduction

Desiraju has defined crystal engineering as “the understanding of intermolecular interactions in

the context of crystal packing and the utilization of such understanding in design of new solids

with desired physical and chemical properties.”1 These understandings are not without

complications: a knowledge gap still exists with respect to controlling the directionality of weak

intermolecular forces,2 which may be further complicated in the presence of stronger, competing

forces.3 While these challenges are known, significant outcomes have resulted from efforts using

hydrogen bonding and coordination chemistry towards the design and synthesis of predictable

assemblies.4 Focusing on hydroxypyridine/pyridone as the dominant source of hydrogen bonding

(Fig. 1a), Wuest reported diamondoid frameworks resulting from the attachment of 2-pyridone

subunits to molecules with tetrahedral cores (Td symmetry tectons), yielding interpenetrating

networks with otherwise enormous voids.5 Architectures resulting from the combination of both

hydrogen bonding and coordination chemistry have also been reported by Turnbull and

colleagues, who have recently been exploring the use of 2-bromo-4-hydroxy-pyridine as a

ligand for coordination with Cu(II), as a means to control intra- and intermolecular structure,

towards magnetic materials.6

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Figure 1. (a) 2-hydroxypyridine/pyridone tautomers; (b) 3,6-dihydroxypyridazine/6-hydroxy-

2H-pyridazin-2-one (maleic hydrazide) tautomers (1,2-dihydropyridazine-3,6-dione not shown);

(c) combined hydrogen bonding motifs in the solid state structures of maleic hydrazide.

In the solid state, maleic hydrazide has been reported in multiple space groups (i.e. multiple

polymorphs; in P-1,7,8 P21/c,9 P21/n8,10), but only in the 6-hydroxy-2H-pyridazin-2-one form

(Fig. 1b). In all cases, it exhibits analogous dimerization to 2-pyridone, with head-to-tail 𝑅22(8)

hydrogen bonding, but also with C=O serving as a double hydrogen-bond acceptor for the

hydroxy-functionality of a third molecule, yielding rings with graph set notation (Fig. 𝑅24(14)

1c). This strong head-to-tail dimerization can be exploited for engineering more elaborate motifs,

if the pyridazine were to be asymmetrically substituted at the hydroxyl position. Of particular

interest to us was the possibility of incorporating groups suitable for metal coordination and the

synthesis of flexible porous motifs (Fig. 2), with a particular focus on first row transition metal

cations with unpaired electrons (for example, Co2+ and Cu2+) for the construction of magnetic

metal-organic frameworks.11

Figure 2. Hypothetical flexible porous motifs from combined hydrogen bonding dimers and

metal coordination (LB = Lewis base functionality for M = metal cation coordination).

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Herein, we report the two step route (Mitsunobu followed by Schiff base reactions) to yield

asymmetrically substituted pyridazinones with the potential for additional intermolecular

interactions via metal cation coordination, all while preserving the original strong hydrogen

bonded dimers.

Experimental

1H and 13C spectra were recorded on an Agilent Technologies Varian Unity Inova 400 MHz

NMR Spectrometer using the indicated deuterated solvents purchased from CIL Int. Chemical

shifts are reported in δ scale using the residual solvent peak as reference. All reagents and

starting materials were purchased from Sigma-Aldrich and used as purchased. Melting points

were determined on a Mel-Temp® Electrothermal melting point apparatus and are uncorrected.

Fourier-transform infrared spectroscopy (FTIR) with attenuated total reflection (ATR) was

performed using a Bruker Alpha spectrometer and spectra were collected using OPUS software.

High resolution mass spectra were recorded at the Centre Régional de Spectrométrie de Masse à

l’Université de Montréal using an Agilent LC-MSD TOF spectrometer. A single crystal of 4 was

selected and collected on a Bruker Apex2 CCD diffractometer. The crystal was kept at 110(2) K

during data collection. Using Olex2,12 the structure was solved with the ShelXT13 structure

solution program using intrinsic phasing and refined with the ShelXL14,15 refinement package

using least squares minimisation.

Synthesis

6-(2-aminoethoxy)pyridazin-3(2H)-one (1): To a three-neck, 250 mL round bottom flask

equipped with an air condenser, under nitrogen gas, was added maleic hydrazide (2.00 g, 17.8

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mmol, 1 equiv.) along with triphenylphosphine (9.90 g, 38.1 mmol, 2 equiv.), and 4 Å molecular

sieves (7 g). A magnetic stir bar and dry toluene (100 mL) was added and the solution left to stir

for approximately 5 minutes. To the flask, diisopropyl azodicarboxylate (DIAD) (7.0 mL, 36

mmol, 2 equiv.) was added dropwise using a 10 mL syringe, followed by ethanolamine (2.1 mL,

35 mmol, 2 equiv.) added dropwise using a 5 mL syringe. The solution was stirred for ~ 2 hours

at rt, then heated to 95 °C (heating mantle) for 12-17 h. Additional ethanolamine (1.0 mL, 17

mmol, 1 eq) was added and the solution was left to cool to room temperature for 1 h and then

was placed in an ice bath for ~ 5 minutes to promote the precipitation of product. The product

was isolated using suction filtration and washed with ice cold CH2Cl2 yielding 6-(2-

aminoethoxy)pyridazin-3(2H)-one (1) as a white solid (1.33 g, 5.45 mmol, 44 %). mp = 160.9-

164.3 °C; 1H NMR (400 MHz, DMSO-d6) δ: 7.15 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H),

3.99 (t, J = 8.0 Hz, 2H), 3.30 (s, 1H), 2.82 (t, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-

d6) δ: 160.0, 153.2, 133.4, 128.2, 69.5, 40.9; IR (ATR, cm-1) ν: 3336, 2957, 2908, 1688, 1630,

1573, 1510, 1311, 1151, 1094, 1009, 903, 863, 802 ; HRMS (ESI+) M = C6H9N3O2; Calc. for

[M+H] +: 156.07675 Found: 156.07699; Calc. for [M+Na] +: 178.0587 Found: 178.05921.

6-(2-{(E)-[(pyridin-X-yl)methylidene]amino}ethoxy)pyridazin-3(2H)-one (2; X=2), (3; X=3),

(4; X=4): To a 100 mL two-neck round bottom flask, equipped with a condenser and drying tube

(CaSO4), was added 1 (0.300 g, 1.9 mmol, 1 eq.) along with a magnetic stir bar, toluene (25 mL)

and 4 Å molecular sieves (4 g). This was stirred for 5 min before the dropwise addition of 2-, 3-,

or 4-pyridinecarboxaldehyde (0.2 mL, 2.1 mmol, 1 eq.), and the mixture was heated to 95 °C (oil

bath) for 12-17 h. The solution was cooled to room temperature, and the molecular sieves were

removed by gravity filtration through a coarse filter (Büchner funnel only; no filter paper.) The

product was isolated using suction filtration (with filter paper) yielding 6-(2-{(E)-[(pyridin-2-

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yl)methylidene]amino}ethoxy)pyridazin-3(2H)-one (2), 6-(2-{(E)-[(pyridin-3-

yl)methylidene]amino}ethoxy)pyridazin-3(2H)-one (3), and 6-(2-{(E)-[(pyridin-4-

yl)methylidene]amino}ethoxy)pyridazin-3(2H)-one (4) at 94%, 98%, and 93% yields

respectively. X-ray quality crystals of 4 were obtained by slow evaporation of solvent (6:1 v/v

toluene/acetonitrile) over the course of 14 days.

(2) 1H NMR (400 MHz, DMSO-d6) δ: 12.19 (s, 1H), 8.65 (d, J = 4.0 Hz, 1H), 8.41 (s, 1H), 7.95

(d, J = 8.0 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 3.9, 4.4, Hz, 1H), 7.13 (d, J = 3.9 Hz,

1H), 6.84 (t, J = 8.0 Hz, 1H), 4.37 (t, J = 8.0 Hz, 2H), 3.98 (t, J = 4.0 Hz, 2H). IR (ATR, cm-1) ν:

1691, 1614, 1301, 1000, 858. Decomposition (melting not observed) > 200 °C; HRMS (ESI+) M

= C12H12N4O2; Calc. for [M+H] +: 245.1033 Found: 245.10429; Calc. for [M+Na] +: 267.08525

Found: 267.08639.

(3) 1H NMR (400 MHz, DMSO-d6) δ: 12.18 (s, 1H), 8.89 (s, 1H), 8.65 (d, J = 4.0 Hz, 1H), 8.49

(s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.48 (dd, 1H), 7.20 (d, J = 4.0 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H),

4.36 (t, J = 3.6 Hz, 2H), 3.94 (t, J = 3.6 Hz, 2H). IR (ATR, cm-1) ν: 1687, 1613, 1001, 849. mp >

260 °C; HRMS (ESI+) M = C12H12N4O2; Calc. for [M+H] +: 245.1033 Found: 245.10311; Calc.

for [M+Na] +: 267.08525 Found: 267.08663.

(4) 1H NMR (400 MHz, DMSO-d6) δ: 12.15 (s, 1H), 8.64 (d, J = 4.0 Hz, 2H), 8.43 (s, 1H), 7.65

(d, J = 4.0 Hz, 2H), 6.82 (t, J = 8.0 Hz, 1H), 4.34 (t, J = 4.0 Hz, 2H), 3.93 (t, J = 4.0 Hz, 2H); );

13C{1H} NMR (100 MHz, DMSO-d6) δ: 162.0, 160.0, 152.9, 150.3, 142.8, 133.6, 128.0, 122.2,

66.3, 59.3. IR (ATR, cm-1) ν: 1685, 1617, 1302, 1033, 868. Decomposition (melting not

observed) > 212 °C; HRMS (ESI+) M = C12H12N4O2; Calc. for [M+H] +: 245.1033 Found:

245.10246.

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Scheme 1. Synthesis of 1-4. No evidence for the formation of 1b was observed.

Results and Discussion

The Mitsunobu reaction is a widely employed route to convert primary and secondary alcohols to

esters, ethers, and other functional groups.16 To now, our literature searches have not revealed

any previous reports of the Mitsunobu reaction performed upon maleic hydrazide. In our hands,

the reaction of maleic hydrazide with ethanolamine under Mitsunobu conditions consistently

yielded the monosubstituted 6-(2-aminoethoxy)pyridazin-3(2H)-one (1). We also attempted the

synthesis of disubstituted 2,2'-[pyridazine-3,6-diylbis(oxy)]di(ethan-1-amine) (Scheme 1; 1b),

however, despite repeated attempts with greater molar equivalents of all reagents except maleic

hydrazide, and various orders of addition for these reagents, the monosubstituted product (1) was

obtained exclusively. This result is not entirely unexpected, due to the known (and observed;

vide infra) propensity for the maleic hydrazide core to exist in the 6-hydroxy-2H-pyridazin-2-one

tautomeric form. Moderate yields of 1 were obtained, owing in part to the challenge of

separating 1 from triphenylphosphine oxide (generated in the course of this reaction).

Towards our goal of design and synthesis of molecules that would maintain the original strong

head-to-tail hydrogen bonding dimer motif (in common with 2-pyridone), but also engage in

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further interactions to yield porous networks, we chose to use ethanolamine when performing the

Mitsunobu step. The product (1) possesses an amine handle for further transformation via Schiff

base reaction with pyridyl aldehydes, to yield terminal groups with Lewis base functionality for

metal coordination (Scheme 1).

Schiff-base reactions of 1 with 2-, 3-, or 4-pyridinecarboxaldehyde resulted in excellent yields of

6-(2-((pyridin-X-ylmethylene)amino)ethoxy)pyridazine-3-ol (2; X=2), (3; X=3), (4; X=4), as

confirmed by 1H NMR and HRMS. A more in-depth study of 4 was pursued with structural

characterization via 2D NMR (see Supplemental Information) and single crystal X-ray

diffraction. For 2-4, 1H NMR and IR results are consistent with the pyridazinone form as the

dominant tautomer, with an N-H singlet observed between 12.1 and 12.2 ppm, and peaks in the

IR between 1691-1630 cm-1 consistent with the presence of C=O stretching, while no frequencies

consistent with the presence of O-H were present. These observations are consistent with

previously reported results for pyridones.17

While 2, 3, and 4 exhibited low solubility in most solvents, multiple attempts to grow single

crystals of 2 and 3 using solvent diffusions and slow evaporation of single and mixed solvents

(including methanol, ethanol, acetonitrile, toluene, hexanes and diethyl ether) were undertaken,

yet yielded only powders. Single crystals of 4 were obtained by the slow evaporation of solvent

over two weeks, from 0.05 g of 4 dissolved in 3 mL of toluene and 0.5 mL of acetonitrile. Single

crystal X-ray data for 4 was processed as a two-component non-merohedral twin with the second

component rotated by 180o around [0.00 0.00 1.00] in reciprocal space, and a volume ratio for

the two components of 0.508(3): 0.492(3). 4 crystallized in the space group P-1, and contained

one molecule in the asymmetric unit (Figure 3).

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Figure 3. Asymmetric unit of 4, represented with 50% displacement ellipsoids.

A search in the Cambridge Structural Database (CSD; Versions 5.04 with Aug. 2019 updates)18

for other structures containing the same O1-C1-N1-N2-C4-X connectivity exhibited by 4 (where

X is a non-metal, excluding hydrogen; NM), where C1-N1-N2-C4 were also part of a six-

membered ring, and no metal coordination or ions were allowed, yielded 268 structures with 401

unique observations (several structures had Z’>1) consistent with a pyridazinone core, and 88

structures with 182 unique observations consistent with a pyridazinol core. It should be noted

that the CSD contained 51 unique reports of 6-hydroxy-4,5-dimethyl-2-phenylpyridazin-3(2H)-

one with Z’=4, hence the large number of observations from a more limited set of structures, and

that in total, 67 structures (including 6-hydroxy-4,5-dimethyl-2-phenylpyridazin-3(2H)-one)

contained elements which satisfied both search criteria, and were included in both search subsets

(though the defined geometries were unique). Table 1 summarizes these results and indicates that

4 is most consistent with pyridazinone character in the solid state.

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Table 1. Selected bond lengths for 4 and Database Observations for Pyridazinones and

Pyridazinols

Observa-

tions

C1-O1 (Å) C1-N1 (Å) N1-N2 (Å) N2-C4 (Å) C4-X (Å)

4

(X=O2)

1 1.247(5) 1.364(5) 1.360(4) 1.286(5) 1.355(4)

Pyridazinone

(X=NM)

401 1.248(29) 1.376(24) 1.366(27) 1.294(30) 1.35(20)

Pyridazinol

(X=NM)

182 1.338(28) 1.283(39) 1.383(29) 1.369(30) 1.269(35)

NM = Non-metal, excluding hydrogen

Molecules of 4 assemble into “head-to-tail” hydrogen bonded dimers (Figure 4; Table 2), 𝑅22(8)

with further close stacking of the pyridazinone moieties to form a second dimer association. This

motif is ubiquitous in reported structures, with a search of the Cambridge Structural 𝑅22(8)

Database for similar motifs (any six membered ring with adjacent N-H and C=O functionality

engaged in interactions with itself or another co-crystallized molecule, for example, maleic

hydrazide with 3-methyluracil19) yielding 3487 structures with 4101 observed D—H•••A

interactions, summarized in Table 2. Hydrogen bonding geometry for 4 are all within one

standard deviation of the database values.

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Figure 4. Hydrogen bonded dimers, and close stacking of pyridazinone moieties. (i) −x, −y+1,

−z+1; (ii) 1−x, 1−y, 1−z.

Table 2. Hydrogen-bond geometry (Å, º) for 4

D—H···A D—H H···A D···A D—H···A

N1—H1···O1i 0.92 (5) 1.90 (5) 2.817 (4) 177 (4)

N—H···O (Defined database

motif; 4101 observations)0.89 (6) 1.98 (10) 2.86 (6) 169 (8)

Symmetry code: (i) −x, −y+1, −z+1.

Examination of extended packing for 4 (Figure 5) suggested that there may be -stacking of the

terminal pyridyl rings parallel to the crystallographic b-axis, however, ring centroid-to-centroid

distances (4.06086(15) Å to 2−x, -1−y, −z and 4.24490(16) Å to 2−x, −y, −z) exceed what is

considered to be any meaningful interaction.

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Figure 5. Extended packing diagram for 4. Pyridyl rings represented as 50% displacement

ellipsoids, and all other atoms represented as capped sticks. Hydrogen atoms omitted for clarity.

Attempts to coordinate 2, 3, and 4 with first row transition metal cations were undertaken using a

variety of methods, including direct combination of ligand and metal salts in heated solvents

(including methanol, ethanol, acetonitrile and toluene) and with the addition of base

(trimethylamine or aqueous sodium/potassium hydroxide), ball milling and microwave reactions.

Despite many efforts, little evidence of coordination was observed (i.e. colour changes or

precipitation upon reaction), and we suspect that this difficulty was in part due to poor ligand

solubility. Colour changes were observed upon reaction of 2 with Cu(ClO4)2, and 4 with CoCl2

or Co(NO3)2, and subsequently, X-ray quality crystals were obtained. Disappointingly, in each

case, these were previously reported (Cu(CH3CN)4(ClO4),20 [CoCl4][Co(DMSO)6]221), or new

solvates ([Co(DMSO)6](NO3)2.2H2O)22 of known metal salts, and no organic ligands were

present.

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Conclusions

We have shown that maleic hydrazide is a suitable substrate for the Mitsunobu reaction, and that

the product of this process is an asymmetric pyridazinone. Our initial goal was to construct

flexible porous architectures by a combination of strong hydrogen bonding dimers and metal-to-

ligand coordination chemistry. We demonstrated that the hydrogen bonding dimer is conserved

in the case of 4, however, construction of porous architectures has so far eluded us. This design

strategy can now be considered for introduction of stronger Lewis base functionality towards our

original goal.

Notes

CCDC 1966083 contain the supplementary crystallographic data for this paper. These data can

be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing

[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12

Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Acknowledgment

LND is grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC),

the Canada Foundation for Innovation, and Wilfrid Laurier University for financial support. This

work was also supported by the Research Support Fund. LKH acknowledges an NSERC

Postgraduate Award (PGS-M) and an Ontario Graduate Scholarship for support. Delara Joekar,

Wilfrid Laurier University, is acknowledged for assistance with collection of IR spectra and

melting point data. Dr. Paul D. Boyle, Department of Chemistry X-Ray Facility, Western

University, London, ON, Canada, is acknowledged for assistance with X-ray data collection.

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(19) Portalone, G.; Colapietro, M. First Example of Cocrystals of Polymorphic Maleic Hydrazide. J. Chem. Crystallogr. 2004, 34 (9), 609–612. https://doi.org/10.1023/B:JOCC.0000044088.22773.fa.

(20) Kiriakopoulos, R.; Boyle, P. D.; Dawe, L. N. CCDC 1968554: Experimental Crystal Structure Determination. CSD Commun. 2019, DOI: 10.5517/ccdc.csd.cc242frf.

(21) Dawe, L.; Rodriguez, C. CCDC 1841060: Experimental Crystal Structure Determination. CSD Commun. 2018, DOI: 10.5517/ccdc.csd.cc1zss1l.

(22) Kiriakopoulos, R.; Boyle, P. D.; Dawe, L. N. CCDC 1901320: Experimental Crystal Structure Determination. CSD Commun. 2019, DOI: 10.5517/ccdc.csd.cc21tgx8.

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Draft

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List of Tables

Table 1. Selected bond lengths for 4 and Database Observations for Pyridazinones and

Pyridazinols

Table 2. Hydrogen-bond geometry (Å, º) for 4

List of Figures

Figure 1. (a) 2-hydroxypyridine/pyridone tautomers; (b) 3,6-dihydroxypyridazine/6-hydroxy-

2H-pyridazin-2-one (maleic hydrazide) tautomers (1,2-dihydropyridazine-3,6-dione not shown);

(c) combined hydrogen bonding motifs in the solid state structures of maleic hydrazide.

Figure 2. Hypothetical flexible porous motifs from combined hydrogen bonding dimers and

metal coordination (LB = Lewis base functionality for M = metal cation coordination).

Figure 3. Asymmetric unit of 4, represented with 50% displacement ellipsoids.

Figure 4. Hydrogen bonded dimers, and close stacking of pyridazinone moieties. (i) −x, −y+1,

−z+1; (ii) 1−x, 1−y, 1−z.

Figure 5. Extended packing diagram for 4. Pyridyl rings represented as 50% displacement

ellipsoids, and all other atoms represented as capped sticks. Hydrogen atoms omitted for clarity.

List of Schemes

Scheme 1. Synthesis of 1-4. No evidence for the formation of 1b was observed.

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Pyridazinones from Maleic Hydrazide: A New Substrate for · 2020-02-25 · 2H-pyridazin-2-one (maleic hydrazide) tautomers (1,2-dihydropyridazine-3,6-dione not shown); (c) combined