Area of Organic Chemistry
Transcript of Area of Organic Chemistry
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 [email protected]://www.unibo.it/sitoweb/daniele.nanni
Prof. Barbara Ballarin, Analytical [email protected]://www.unibo.it/sitoweb/barbara.ballarin
Prof. Maria Cristina Cassani, Inorganic [email protected]://www.unibo.it/sitoweb/maria.cassani
Dr. Francesca Gambassi, PhD [email protected]
Dr. Ilaria Ragazzini, PhD [email protected]
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: [email protected]
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:[email protected]@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:[email protected]
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 [email protected] Prof. Letizia Sambri [email protected]
Available Positions: One from october 2020 and Two starting march 2021