Area of OrganicChemistry

Dept. of Industrial ChemistryUniversity of Bologna

Area of Organic Chemistry - membersPermanent positions (11):

Prof. Andrea Mazzanti full professorProf. Giorgio Bencivenni associate professorProf. Luca Bernardi associate professorProf. Mauro Comes Franchini associate professorProf. Mariafrancesca Fochi associate professorProf. Daniele Nanni associate professorProf. Paolo Righi associate professorProf. Letizia Sambri associate professorProf. Carla Boga associate professorProf. Emanuela Marotta assistant professorProf. Paolo Zani assistant professor

RTD-B (senior researcher): Dr. Michele Mancinelli

PhDs: 3-4 post-docs: 3-4 post-grad grants: 1-2Master Thesis internships: 8-10

Main area and department research facilities

• NMR spectrometers (300 MHz, 400 MHz, 600 MHz)

• Analytical HPLC on chiral stationary phase

• Preparative HPLC also on chiral stationary phase

• VCD-ECD

• MS spectrometers (GC-MS, ESI);

• Single-crystal X-Ray diffractometer (access to powder XRD);

Topics & Laboratories- Development of nanostructured systems based on metallic nanoparticles

(CHINANOR-Nanni)- Composite materials for energy storage and sensing applications

(CHINANOR-Nanni)- Metal organic frameworks (MOFs) - suitable porous materials for catalytic

application (CHINANOR-Nanni)

- History of chemistry through XVIII and XIX centuries – chemistry as «scientianova» (Zani)

- Development of new catalytic enantioselective reactions (OCSA-Bernardi-Fochi)

- «Blue chemistry»: marine biopolymer gels in catalysis (OCSA-Bernardi-Fochi)

- New organocatalytic enantioselective vinylogous reactions (OCSA-Bencivenni-Marotta-Righi)

- Organocatalytic enantioselective formation of atropisomers (OCSA-Bencivenni-Marotta-Righi)

Topics & Laboratories

- Synthesis of compounds as anticancer agents and related studies on their drug delivery (Boga)

- Synthesis of highly conjugated organic compounds for applications in optoelectronic field (Boga)

- Detection of labile intermediates of aromatic substitution reactions (Boga)

- DFT Calculations (OCSA-Mancinelli-Mazzanti)- Structural analysis (OCSA-Mancinelli-Mazzanti)

- Additive Manufacturing (3D-Printing) (ASOM-Comes-Sambri)- Bio-Ink for biomedical applications (ASOM-Comes-Sambri)- Theranostic: Therapeutic + Diagnostic (ASOM-Comes-Sambri)- Sensing for organic electronics (ASOM-Comes-Sambri)

Department of Industrial Chemistry «Toso Montanari», Viale Risorgimento 4, BO, IT-40136web site: https://chimica-industriale.unibo.it/it/ricerca/gruppi-di-ricerca/chinanor

Prof. Daniele Nanni, Organic chemistrydaniele.nanni@unibo.ithttps://www.unibo.it/sitoweb/daniele.nanni

Prof. Barbara Ballarin, Analytical Chemistrybarbara.ballarin@unibo.ithttps://www.unibo.it/sitoweb/barbara.ballarin

Prof. Maria Cristina Cassani, Inorganic Chemistrymaria.cassani@unibo.ithttps://www.unibo.it/sitoweb/maria.cassani

Dr. Francesca Gambassi, PhD studentfrancesca.gambassi2@unibo.it

Dr. Ilaria Ragazzini, PhD studentIlaria.ragazzini6@unibo.it

CHINANOR Nanomaterials is a multidisciplinaryteam made by three researchers with consolidate skills in CHemistry, in particular in the field of INorganic, ANalytical and ORganic chemistry.

Topics:planning, synthesis and characterization of new nanostructured materials for catalytic, environmental and energetic applications.

«only a 360 degrees knowledge of materialsallows to take full advantages from their

properties»

Development of nanostructured systems based on metallic nanoparticles

This aspect of research develops synthetic/electrosyntheticprocedures to obtain nanostructured systems based on metallicnanoparticles (Au, Ag, Pt etc.) supported on different substrates(silica, allumina, titania, magnetite, hydrotalcite, cellulose, etc.)funzionalized with organic residues.The obtained systems, completely characterized from the chemical-phisical point of view, are used as:a) catalysts for some organic syntheses;b) applications in the environmental and cosmetic field.

Fe3O4

Au

Au

AuAu

AuAu

Au Au

Au Au Au Au

Au/SiO2@Yne

THE NANOWORLD FOR INDUSTRIAL APPLICATIONS

HAuCl4

PMMA

COMPOSITE MATERIALS FOR ENERGY STORAGE AND SENSING APPLICATIONS

The goal of this kind of research is to find more environmentalfriendly sistems for future industrial applications. The research canbe devided into two main topics:

1. Energy storage applications: electrodepositation of thin filmsbased on conductive polymers modified with different kind ofnanoparticles like inorganic oxides, and the study of theirproperties with the aim of making devices able to store energy;

2. Paper electronics: modification of bare fibers of cellulose withconductive polymers to create materials with high conductivityand flexibility to make smart and cheap sensors with differentapplications (touch sensors and gas sensors for example).

Bare cellulosic

fibers

Modifiedfibers

METAL ORGANIC FRAMEWORKS (MOFs) - SUITABLE POROUS MATERIALS FOR CATALYTIC APPLICATION

Development of MOFs systems containing gold nanoparticles.The Aim of this project in three key steps:

• Synthesis of new organic linker able to react withcopper ions leading to the construction of a new, porous crystalline material Cu-MOF.

• Characterization of the new material by means ofseveral complementary techniques such as NMR spectroscopy, IR-ATR spectroscopy, atomic absorptionspectroscopy (AAS), thermogravimetric analysis(TGA), Raman analysis.

• Realization of a useful platform with high surfacearea capable of hosting gold nanoparticles due to hisporosity and his organic funcionality, with promisingcatalytic capacities.

Metallic kinkFor create a specific geometryAnd for possiblebifunctionalcatalysis

Organic linkerfor the construction ofCu-MOF and the support of Au-NPs

Hosted speciesWith special catalyticproperties for variousorganic reaction

Cu-MOF

• Prof. Carla Boga, Dipartimento di Chimica Industriale «Toso Montanari»: Preparation of new magnetic nanoparticles coated with (R)-9-Acetoxystearic Acid for Biomedical Applications.

• Università Politecnica delle Marche: preparation of inorganic/organicscintillators.

• Dipartimento di Chimica "Giacomo Ciamician", Università di Bologna: XRD,TGA, TEM.

• Dipartimento di Scienze Chimiche e Farmaceutiche, Universita di Ferrara: FlowChemistry.

• Dipartimento di Scienze Chimiche, Università di Padova: XPS, FE-SEM.

• Consiglio Nazionale delle Ricerche di Bologna e Faenza.

Collaborations

History of sciences (Zani)

Development of chemistry through XVIII and XIX centuries:

Chemistry as «scientia nova», a methodological and documentalapproach.

For information: paolo.zani@unibo.it

Research topics – OCSA (Bernardi-Fochi)

1) Development of new catalytic enantioselective reactions:Using known organic catalysts (different classes), we explore new chemistryand reactivity.

H-Bond and bifunctional catalysts

O

OP

O

O

Ar

Ar

H

N

R

N NH

H

N

O

OH

R

Aminocatalysis

NH

ArAr

OTMS

NH

NO

Ph

Phase-Transfer Catalysis

N

R

NH

HO X-

R

Synergistic Catalysis

O

OP

O

O

Ar

Ar

H+ [Pd]

-Dearomatization of activated pyridines:

N

R

Ewg

N

R

EwgNu H

piperidines

-aza-Diels-Alder cycloadditions:

R1

N + R3 NH

R1

R2R2

R3

A student involved in such a project will learn how to:-perform multi-step organic synthesis (catalysts and substrates)-characterise organic compounds (NMR, HPLC analysis)-perform extensive optimisation of reactioncoinditions.

For additional information:luca.bernardi2@unibo.itmariafrancesca.fochi@unibo.it

Research topics – OCSA (Bernardi-Fochi)

1) Purification2) Acidification and gelification3) From hydrogel to solvogel to aerogel

Aerogel:Same properties of a gel (surface are 600 m2g-1)All functionalities are accessible

2) «Blue chemistry»: marine biopolymer gels in catalysis:Aginate biopolymers (algae extracts) readily form gels (solvogels, aerogels) with high surface areas and functional group density: applications in catalysis and adsorption.

Adsorption

S

N

NNCl

Currently pursued: is it possible to exploit the intrinsichomochirality for enantioselective processes?

A student involved in such a project will learn how to:-perform simple organic synthesis-prepare and manipulate hydro and solvogels-characterise organic compounds (NMR, HPLC analysis)-perform extensive optimisation of reaction coinditions

For information:luca.bernardi2@unibo.it

mariafrancesca.fochi@unibo.it

Research topics – ORG (Bencivenni*-Marotta-Righi)

3-Collaboration with fine chemical SMEs:

FATRO S.p.A. - VeterinaryPharmaceutical Industry40064 Ozzano dell’Emilia (BO) Italy

1 PhD student1-3 Master (6-9 months) students2-3 Bachelor (3-6 months) students1 post-doc1 industrial granted position

Endura S.p.A. - PBO and synthetic pyrethroidsHeadquarters in Bologna, manufacturing and R&D in Ravenna

1 - New organocatalytic enantioselectivevinylogous reactions:

NH

O

H

BH

NH

O-

-BH

dienolate forms

γγ'

H

NH

O-

s-ciss-trans

γ'-site pathway γ-site pathway

2 – Organocatalytic enantioselectiveformation of atropisomers:

Research topics – (Bencivenni-Marotta-Righi)1) New organocatalytic enantioselective vinylogous reactions:• Vinylogous reactivity is a valuable strategy for the remote modification of a molecule.• Vinylogous addition of alkylidene oxindole on aryl trifluoromethyl ketone resulted in a rare

aldol reaction-lactonization cascade. The reaction, catalyzed by a bifunctional tertiary amine, provides an efficient entry to enantioenriched trifluoromethylated α,β-unsaturated δ-lactones.

• The addition on α,β-unsaturated trifluoromethyl ketones provided an efficient preparation of enantioenriched trifluoromethylated allylic alcohols

NO

R'

Boc

THF, rt, 24 h

cat (10 mol%)

up to 88% yieldup to 95% ee

PhCF3, rt, 72 h

cat (10 mol%)

O

ONHBoc

up to 99% yieldup to >99% ee

RCF3

Ar

Ar

O

CF3

O

CF3Ar

NO

R'

Boc

HOCF3 Ar

N

NHN

O

NH

S

H

Ar

Ar = 3,5-(CF3)2-C6H3

I-9-epi-HQAT

Aldol Lact Aldol

Bencivenni, et al. J. Org. Chem. 2018, 83, 12440.Bencivenni, et al. RSC Adv., 2018, 8, 33451

Research topics – (Bencivenni-Marotta-Righi)2) Organocatalytic enantioselective formation of atropisomers:• Enantioselective organocatalysis has been successfully applied to the synthesis of atropisomers• Desymmetrization of N-arylmaleimmides by nucleophilic attack on their prochiral double bond

afforded atropisomeric succinimides

• Axially chiral cyclohexylidene oxindoles were selectively obtained by means of organocatalytic Knoevenagel condensation. Insights on the mechanism were obtained by DFT methods

Bencivenni, et al. Synthesis, 2017, 49, 1513.NO

Boc

N

O

H ON

O

Boc

NO O+

catalyst J (10 mol%)

CH2Cl2 [0.25M]

25 °C, overnight

R1

R2 R3

R1

R2

R3

tetrasubstituted carbon stereocenter

trisubstituted carbon stereocenter

atropisomeric C-N axes

NH

O

N

NH

HNO

O

F3C CF3

NH

O +HN

OH

Ph

H

PhOR

R1

R2

R1R

R2Im

Enantioselective axially chiral Knoevenagel condesation

Axially chiral cyclohexylidene

H

PhN∗ HH

RO

ON

∗

OHH

R

OO

H

Bencivenni, et al. Org. Lett., 2019, 21, 3013.

Synthesis of compounds as anticancer agents and related studies on their drug delivery

It acts as an inhibitor of enzymes belonging to the hystonedeacetylase classes. Recently the interest has been focused on itsdrug-delivery: it has been succesfully inserted in hydroxyapatitenanoparticles (Langmuir 2016), Keratine nanoparticles (Mol Pharm2019) and, more recently, in magnetite nanoparticles (ACS Omega, in press). (R)-9-HSA behaves as organogelator, an interestingproperty in material field (Molecules, 2019). Also the synthesis of structural hybrids bearing the HSA scaffold is work in progress.

OH

HO H

78

O

Dimorphotheca sinuata

RECENT PUBLICATIONS

Boga, C. et al.: Redox signaling via lipid peroxidation regulates retinal progenitor cell differentiation. Developmental Cell 2019, 50, 1-17.

Boga, C. et al.: X-Ray Crystal Structures and OrganogelatorProperties of (R)-9-Hydroxystearic Acid. Molecules 2019, 24 (15), 2854.

Boga, C. et al.: Unprecedented behavior of (9R)-9-hydroxystearic acid loaded keratin nanoparticles on cancercell cycle. Mol. Pharmaceutics 2019, 16, 931-942.

Boga, C. et al.: Synthesis of 9-Hydroxystearic Acid Derivatives and Their Antiproliferative Activity on HT 29 Cancer Cells. Molecules 2019, 24, 3714.

(R)-9-HSA is an endogenous cellular lipid that, when administered to different human cancer cell lines (colon, bone, leukemia cells, etc.) produces tumor cell growth arrest without effect on normal cell lines.

(R)-9-hydroxystearic acid

Synthesis of (R)-9-hydroxystearic acid [(R)-9-HSA] and its derivatives(R)-9-HSA can be obtained in high yield from Dimorphotheca sinuata seed oil through a simple multistep procedure.

Recent studies have been devoted also on the synthesis of novel compounds as substitutes of APCIN in the treatment of acute myeloid leukemia.

CollaborationsIstituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Meldola (FC)Dipartimento FABIT – University of Bologna.Dipartim. Di Chimica e Scienze Farmaceutiche. Univ. Trieste

Research topics – (Boga)

Synthesis of highly conjugated organic compounds for applications in optoelectronic field

Synthesis and properties of solid state fluorescentmaterials

OCH3H3CO

Y

N2+

+

O

O ON

N

Y

BF4-

OCH3X Z

ZX

HBF4

CH3CNRT

Novel highly conjugated architectures from C–C coupling between aminothiazoles, diamino- or sym-triamino-benzenes and benzofurazan- or benzofuroxan- derivatives.

Boga, C. et al.: New azo-decorated N-pyrrolidinylthiazoles: synthesis, properties and an unexpected remote substituent effecttransmission Org. Biomol Chem 2016,14,7061-7068.

Boga, C. et al.: Coupling Reactions between BenzofurazanDerivatives and 1,3-Diaminobenzenes. Molecules 2017, 22, 684.

Boga, C. et al.: Highly conjugated architectures and labile reactionintermediates from coupling between 10π electron-deficientheteroaromatics and sym-trihydroxy- or triaminobenzenederivatives.” RSC Adv., 2018, 8, 41663-41674.

Recent and current topic:Synthesis of organic compounds for applications as scintillators

Collaborations

Istituto per la sintesi organica e la fotoreattività (ISOF-CNR Bologna)Proff. Nanni, Cassani, Ballarin (CHIMIND)Dipartimento di Fisica e Ingegneria dei Materiali e del Territorio, Universita Politecnica delle Marche.

Research topics – (Boga)

Detection of labile intermediates of aromatic

substitution reactionsThe C-C coupling between strongly activated aromatic neutral nucleophiles (Nu) and electrophiles (E) allowed the

first detection and characterization of Wheland-Meisenhemer (WM) intermediates, contemporarily of the SEAr

(Wheland) and of the SNAr (Meisenheimer) (Boga, C. et al.: Angew.Chem. 2005, 44, 3285-3289).

This paved the way to many other examples, with different Nu/E combinations and the topic is yet in progress.

G

G GH E

+ X–

Wheland (W) have also been detected

G G

G

+ E+X–

WG = electrondonor groupE+X– = benzenediazonium saltE+BF4

– = benzhydrilium tetrafluoroborate (incollaboration with Prof.Herbert MayrDepartment Chemie -Ludwig-Maximilians-Universität München

NO

NNR2R2N

NR2

O2N

NO2

O

+N

ON

NO2

O2NH O

NR2R2N

NR2

H

NR2 =

N-piperidinyl, N-morpholinyl, N-pyrrolidinyl

-

Zwitterionic Wheland-Meisenheimer intermediate (WM)

DNBF

Neutral carbon superelectrophile

Neutral carbon supernucleophile

Other WM from the following combinationsNu = sym-triaminobenzenes, E = 4,6-dinitrotetrazolepyridine (DNTP) (JOC 2009)Nu = sym-triaminobenzenes, E = 2,3,4-trinitrothiofene (Org. Biomol. Chem. 2016)Nu = 2-aminothiazole E = DNBF (Chem. Eur. J. 2007)Nu = 2,4-dipyrrolidinylthiazole E = DNBF e DNTP (Eur. J. Org. Chem. 2012)

Research topics – (Boga)

Synergistic Catalysis: Highly EnantioselectiveAcetyl Aza-arene Addition to Enals

Chem. Eur. J. 2018, 24, 13306-13310

Research topics – (Mazzanti - Mancinelli)

DFT Calculations

The zinc enolate can approach the iminiumion in an ’’endo’’ geometry driven by a morefavorable interaction between the HOMO ofthe enolate and the LUMO of the iminiumion, with the zinc and the nitrogen of theiminium ion involved in the HOMO-LUMOinteraction. This geometry is more stablethan the ’’exo’’ by more than 3 kcal/mol, andit accounts for the formation of the Senantiomer when R-catalyst is used (Fig 1)

The TS involving the second addition issimilar to that of the first step with the Egeometry of the iminium ion. Again the endogeometry with zinc over the nitrogen isfavored with respect to the exo, and the moststable TS involves the attack the Re face ofthe zinc enolate. This TS forges the secondstereocenter with S-configuration. (Fig 2)

Research topics – (Mazzanti - Mancinelli)

Research topics – (Mazzanti - Mancinelli)

Structural analysis

TD-DFT calculation of ECD spectrum

DFT optimization

Experimental ECD

Conformational analysiswith MM

NOE-NMR experiments

2D-COSY experiments

Relative configuration

Conformation

Absolute configuration

Research topics – (Mazzanti - Mancinelli)

H-3

H-9

H-1H-13

{H-2}

H-7

H-13H-9

H-2 H-3H-1

H-6b H-6a

H-5

Absolute configuration3i-minor 1S,2S,3S

-20

-15

-10

-5

0

5

10

15

20

25

30

35

190 210 230 250 270 290 310 330 350 370 390nm

mdeg

3i-major3i-minor

N

2

O

3

1

O

NC

CN

3i-major

N

2

O

3

1

O

NC

CN

3i-minor

mdeg

3i-minor1S,2S,3S

nm

Relative configuration3i-minor 1S*,2S*,3S*

1

23

4

56

7

O16

17

O

1819

20

21N

12

15

1413

89

1011

NC

CN

3i-minor

Example for Compound 3i-minor

CD3CN at +25 °C

600 MHz in CDCl3at +25 °C

NOE-NMR

1H-NMR

Experimental ECD spectrum

TD-DFT ECD spectra

6-311++G(2d,p)

600 MHz in CDCl3at +25 °C

Research topics – (Mazzanti - Mancinelli)

Chemodivergent Preparation of Multiple Heterocycles via Phase-Transfer Catalysis: Enantioselective Synthesis of Functionalized Piperidines

XO

MeMeO2C

Electrophilic sites

Tetheringheteroatom

Pathway aX

OH

MeArS

CO2Me

piperidinesthianesTHpyranes

Pathway b

X

O CN

Me

CO2Me

morpholines1,4-oxathianes1,4-dioxanes

Pathway c

X

OH

Me

NC CNMeO2C

-Exploiting the pluripotency of substrates 1 with PTC: chemo-divergent synthesis of heterocycles

1

piperidinesTHpyranes

-Nucleophile directs the pathway

-DFT calculations explainthe chemo-divergency (a) vs

(b)

-Asymmetric catalysis: enantioentiched piperidines

ArSH

"-CN"

CNNC

NTs

ArSCO2R2

R1

OH

enantioenrichedpiperidines

23

4

5

Research topics – (Mazzanti - Mancinelli)

NMs

O OMe

O

TMA

NMs

PhSMe

O

O OMe

TMA1a*

Activatedcomplex

PhS

NMs

PhSMe

O

O OMe

TMA

NMs

PhSMe

O

O OMe

NMs

PhSMe

O

O OMe

3aa*

observed, major

H2O

-TMAOH

3'aa*

observed, minor

H2O

-TMAOH

3''aa*

not observed

H2O

-TMAOH

3'''aa*

not observed

H2O-TMAOH

TSA

TSB

TSC

TSD

IntA

IntB

IntC

IntD

(R*)

(R*)

(R*)

(S*)

(S*)

(R*)

(R*)

(S*)

(R*)

(S*)

(R*)

(R*)

TMA

TMA

Pathway A

Research topics – (Mazzanti - Mancinelli)

Int2(R*,S*)A

TS1B

TS2B

Int2B

8.610.8

17.0

14.0

Activated complexesA (0.0) and B (0.4)

16.3

Int1B

-6.5

-14.8

1.4

TS1A

4.5

TS2(R*,S*)A

TS2(R*,S*)A

Int2(R*,S*)A

3.2Int1

A

4a*-3.0

-2.04’a*

+TMAOH-H2O

+TMAOH-H2O

MeO

OMsN

Me

O CNCN

NMs

CNO

Me

MeO ONMs

OMe

CN

O

MeO

NMs

OMe

CN

O

MeO

TMATMATMA

TMA

TMA

NMs

NC

O OMe

O

TMA

NMs

NCMe

O

O OMe

TMA

TS1A

Int1A

TS2(R*,R*)A

(R*) (S*)

Int2(R*,S*)A

not observed

H2O

-TMAOH

(R*) (R*)

H2O

-TMAOH

4a*

4'a*

TS2(R*,S*)A

TS1B

observed

Int2(R*,R*)A

TS2B H2O

-TMAOH NMs

NCMe

OH

O OMe

Int1B Int2Bnot observed

4''a*

Activatedcomplex B

Activatedcomplex A

1a*

Pathway BResearch topics – (Mazzanti - Mancinelli)

The research group activity is focused on the optimization of innovative processing techniques with the aim of developingnew organic materials for applications in the field of nanomedicine and organic electronics, for industrial applications.

Processing techniques include:

• Additive Manufacturing (3D-Printing) in order to obtain new materials starting from natural pool sources, such ascarbohydrates and proteins. The starting biomaterials are synthetically modified before being applied to themanufacturing.

• Bio-Ink for biomedical applications via gel-extrusion deposition. Here too, biocompatible materials are investigated:the formulations are thoroughly explored and optimized in order to obtain suitable rheology for building scaffoldseligible for Tissue Engineering.

The group has proven expertise in synthesis of luminescent molecules and organic functionalization of metal-conductiveand piezoelectric nanostructures (gold, silver, metal oxides) with different size and shapes. Integration of these featureswith the above-mentioned Processing Techniques give main applications as:

Theranostic (Therapeutic + Diagnostic) in biomedical field. European project undergoing https://chimica-industriale.unibo.it/it/ricerca/progetti-di-ricerca/novel-precision-technological-platforms-to-promote-non-invasive-early-diagnosis-eradication-and-prevention-of-cancer-relapse-proof-of-concept-in-the-bladder-carcinoma

Sensing for Organic Electronics.

Advanced Smart Organic Materials (ASOM)WEB: https://chimica-industriale.unibo.it/it/ricerca/gruppi-di-ricerca/advanced-smart-organic-materials-asom

Contact: Prof. Mauro Comes Franchini mauro.comesfranchini@unibo.it Prof. Letizia Sambri letizia.sambri@unibo.it

Available Positions: One from october 2020 and Two starting march 2021