Hydrogen-Bond Donor:
Urea/Thiourea

Who discovered hydrogen bond??

Literature Seminar
Haruka Ida
2012.12.17 (Mon.)
1

Contents
1. Introduction
Hydrogen bond
Organocatalyst
Urea/Thiourea
2. Organocatalysis
Pioneering Studies
Recognizing Carbonyl
Nitro Group
Sulfonate
Hydrogen Cyanide
3. Material
4. Bioactive compound
5. Summary

2

Contents
1. Introduction
Hydrogen bond
Organocatalyst
Urea/Thiourea
2. Organocatalysis
Pioneering Studies
Recognizing Carbonyl
Nitro Group
Sulfonate
Hydrogen Cyanide
3. Material
4. Bioactive compound
5. Summary3

About Hydrogen bond (H-bond)

1. Introduction

Who discovered H-bond??
--T. S. Moore and T. F. Winmill‘The state of amines in aqueous solution’J. Chem. Soc. Trans. 1912, 101, 1635.
H-bond has the 100-year history .
The hydrogen bond is an attractive interaction between a hydrogen atom from a molecule ora molecular fragment X–H in which X is more electronegative than H, and an atom or a groupof atoms in the same or a different molecule in which there is evidence of bond formation.
--D. J. Nesbitt, et al, IUPAC Technical Report(http://media.iupac.org/reports/provisional/abstract11/arunan_tr.pdf)

Properties of H-bond.

Urea/Thiourea
Mark S. Taylor and Eric N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520.

41. Introduction

H-bond in Nature
CIC chloride channel

Chloride ion
・regulates membrane potentials.
・is stabilized by electrostaticinteractions with α-helix dipoles
and by chemical coordination
with amino and hydroxyl groups.

serine protease• A class of enzymes characterized by auniquely reactive serine side chaincleaving peptide bonds in proteins.
• Stabilizing the oxyanion.
R. MacKinnon, et al, Nature 2002, 415, 287.
L. Hedstrom, Chem Rev. 2002, 102, 4501.
5

Organocatalyst

1. Introduction

Organocatalyst• Consist of elements like carbon, hydrogen, oxygen, nitrogen, sulfur and so on, notincluding any metal.
• Have low molecular weight.
• Possess the function catalyst.

Advantages:• The reactions can be performed under an aerobic atmosphere with wet solvents.
(Organocatalysts are often more stable than enzymes or metal catalysts. )• The catalysts are inexpensive.
• They can be anchored to a solid support and reused more conveniently thanorganometallic/bioorganic analogues, and show promising adaptability to highthroughput screening and process chemistry.

6

Representative H-bond donor catalysts.

1. Introduction

Mark S. Taylor and Eric N. Jacobsen, Angew. Chem. Int. Ed. 2006, 45, 1520.

7About Urea/Thiourea 1

1. Introduction

pKa

cf. Phenol: 9.95

F. G. Bordwell, et al, J. Am. Chem. SOC. 1991, 113,8398.
P. R. Schreiner, et al, Org. Lett. 2012, 14, 1724.

8

About Urea/Thiourea 2

1. Introduction

Conformational Preference of N,N’-diarylurea

M. Helliwell, et al, Phys. Chem. Chem. Phys. 2010, 12, 15064.

9Contents
1. Introduction
Hydrogen bond
Organocatalyst
Urea/Thiourea
2. Organocatalysis
Pioneering Studies
Recognizing Carbonyl
Nitro Group
Sulfonate
Hydrogen Cyanide
3. Material
4. Bioactive compound
5. Summary

10Pioneering Study of Activation of Electrophile 2. Organocatalysis
Using H-Bond --Hine
Biphenylenediol-Promoted Epoxide-Opening Reaction

pKa
9.95
8.00
J. Hine, et al, JACS 1985, 107, 1082.

1,8-biphenylenediol has two H-bond donor
and make oxygen atom negative effectively.

Fig. ORTEP drawing displaying the labeling scheme and bond distances (A)for the 1,8-biphenylenediol-1,2,6-trimethyl-4-pyridone complex with nonhydrogen atoms drawn at the 50% probability level and hydrogen atoms
drawn with an artificial radius. The estimated standard deviations on thebond distances are 0.003-0.004 A.
J. Hine, et al, J. Am. Chem. SOC. 1984, 106, 7980.
11

Early Example of the Reaction
with Recognition of Carbonyl group --Kelly

2. Organocatalysis

Diels-Alder Reaction: Rate Acceleration Promoted By A Biphenylenediol

pKa 6.1

Roles of acids in Diels-Alder Reaction• Lower LUMO of dienophile and improve the regioselectivity.
Characteristics of 8• Superior to acidic monodentate H-bond donor(such as p-nitrophenol, 4-nitro-3-(trifluoromethyl)phenol).
T. R. Kelly, et al, Tetrahedron Lett. 1990, 31, 3381.

12

Activation of Dienophile with Thiourea

2. Organocatalysis

Diels–Alder Reaction

The energy barrier with 4was smaller than thatwithout 4 by 2 kcal/mol.
P. R. Schreiner, Chem. Soc. Rev.
2003, 32, 289.
Fig. The Diels–Alder reaction of 1 and 2 uncatalyzed and catalyzed by 4. The energies at the B3LYP/631+G**//AM1 level relative to the starting materials are given in kcal/mol (the SCRF-energies are in
13
parentheses, NBO-charges in italics). Some of the hydrogens were removed for clarity.

Activation and Cyanation of Carbonyl 1

2. Organocatalysis

Optimized Catalyst and Equilibrium

Equilibriumin ketone cyanosilylation.

E. N. Jacobsen, et al, J. AM. CHEM. SOC. 2005, 127, 8964.
E. N. Jacobsen, et al, J. AM. CHEM. SOC. 2007, 129, 15872. 14

Activation and Cyanation of Carbonyl 2

2. Organocatalysis

Relationship between Reaction Rate and Concentration of HCN
HCN• Without HCN → No reaction.
• 15 mol% HCN → Sufficient toeffect >90% substrate conversion.
• High [HCN] → Rate inhibition.
(15 mol%)
Fig. Rate dependence on [HCN].
Plot of the rate of cyanosilylation of 6b ([6b]i = 0.33 M)
with TMSCN ([TMSCN]i= 0.50 M) catalyzed by HCN and1a (0.025 M) at different [HCN] and at different
conversions of 6b.

E. N. Jacobsen, et al, J. AM. CHEM. SOC. 2007, 129, 15872.

15

Activation and Cyanation of Carbonyl 3

2. Organocatalysis

Relationship between Reaction Rate and Concentration of Catalyst
HCNThe reaction rate displays a lessthan first-order dependence on[1a] at elevated catalyst
concentrations.

Fig. Rate dependence on [1a]. Plot of the rate of
cyanosilylation of 6b ([6b]i = 0.33 M) with TMSCN([TMSCN]i = 0.50 M) catalyzed by HCN (0.33 M) and 1aat different [1a] and at different conversions of 6b.

(*First-order dependence on [6])E. N. Jacobsen, et al, J. AM. CHEM. SOC. 2007, 129, 15872.

16

Activation and Cyanation of Carbonyl 4

2. Organocatalysis

Possible Transition States
Mechanism A was more favorable than B (4.7 kcal/mol).
Mechanism B:• Lower nucleophilicity of cyanide anion.
• Smaller activation of carbonyl with mono H-bond.

(Thiourea recognize carbonyl.)(Thiourea recognize cyanide.)
E. N. Jacobsen, et al, J. AM. CHEM. SOC. 2007, 129, 15872.

17

Activation and Cyanation of Carbonyl 5

2. Organocatalysis

Decision of Steric Configuration
TS in mechanism A

0.9 kcal/mol

Conclusive factor of the enantioselectivity:
Repulsive interactions between the amide π-system and the substrate π-system.
Sharp decreases in enantioselectivity were observed when using electrondeficient acetophenone
derivatives.
18E. N. Jacobsen, et al, J. AM. CHEM. SOC. 2007, 129, 15872.

Recognition of Nitro Group 1

2. Organocatalysis

Biomimetic Reduction of Conjugated Nitroalkenes

Only nitrostylene interact with 3strongly enough to be reduced.

Hantzsch esters

Z. Z. Peter R. Schreiner, Synthesis 2007, 16, 2559.

They were inspired by NADH system.
Nicotinamide adenine dinucleotide(NADH) is a coenzyme to reduce
unsaturated functionalities under very
mild conditions.

NAD+ 19

Recognition of Nitro Group –Michael Reaction 2-1
Substrate Scope

Y. Takemoto, et al, J. Am. Chem. Soc. 2005, 127, 119.

20

Recognition of Nitro Group –Michael Reaction 2-2
Mechanistic Studies

Transition-state models of Michael reactionsof malonate.

1H-NMR investigation:

Ha: 6.63 to 6.67 ppm
Hb: 7.31 to 7.35 ppm

Kinetic study:
The reaction is first-order incatalyst (1e), nitrostyrene (2a)and maronate (3a).

B is favorable to C due to the steric hinderance.
Y. Takemoto, et al, J. Am. Chem. Soc. 2005, 127, 119.

21

Recognition of Sulfonate –Povarov Reaction 1

2. Organocatalysis

Structure-Reactivity/Enantioselectivity Studies• Urea derivative showed better enantio- and diastereoselectivity than thiourea(catalyst 1a vs. 1b).
• The position of sulfonic amide O was important (1a vs. 1c).
• Phosphinic amide urea, pivalamide urea and amino urea
induced both low reactivity and selectivity (1a vs. 1d,1eand 1f).
E. N. Jacobsen, et al, Science 2010, 327, 986.

22

Recognition of Sulfonate –Povarov Reaction 2

2. Organocatalysis

Geometry and energy-minimized structures

B: All four intermediates (I to IV) were expected beenergetically accessible.

About I’ vs. II’

But nucleophile added, I’ was predicted to have over
1.3 kcal/mol lower energy than the other complexes.
(Because of the π-π interaction (I’ vs. II’) and theroom around the reactive sites(I’ vs. III’, IV’)).
I’

I, II, III and IV + dihydrofurane → I’, II’, III’ and IV’.
E. N. Jacobsen, et al, Science 2010, 327, 986.

23

Activation of Hydrogen Cyanide --Strecker Reaction 1-1
Catalyst Optimization and Comparison Substrates
α-Amino acids are the building blocks of proteins and are widely used as components ofmedicinally active molecules and chiral catalysts.

P. Vachal and E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012. 24

Activation of Hydrogen Cyanide --Strecker Reaction 1-2
Solution structure of Catalyst and Aldimine

The large group on the imine
carbon is directed away fromthe catalyst and into solvent.
The N-substituent is also
directed away from the catalyst.

!!!
HCN was absent
from this condition.
Fig. Solution structure of catalyst 1(B, C) two views of the complex generated uponbinding of a Z-imine, as determined

The small group is aimed
directly into the catalyst.

P. Vachal and E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012. 25

Activation of Hydrogen Cyanide --Strecker Reaction 2-1
Improvement in 2009 Nature

E. N. Jacobsen, et al, Nature 2009, 461, 968.

26

Activation of Hydrogen Cyanide --Strecker Reaction 2-2(Mechanistic Study) Via Cation or Anion ??

Figure 4. Rate dependence of imine hydrocyanation catalyzed by 4aor 4b on substrate electronic properties. Plot of the logarithm ofpseudofirst-order rate constant (log(kobsd)) versus σp for thehydrocyanation of p-substituted imines 2b-2g ([2]i =0.040 M) byTMSCN/MeOH (0.50 M) mediated by thiourea catalyst 4a ([cat]tot )0.0020 M, ●) or urea catalyst 4b ([cat]tot ) 0.0020 M, ▲) versus σp.

Hydrocyanation proceeded via cation species.
S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131, 15358.

27

Activation of Hydrogen Cyanide --Strecker Reaction 2-3(Mechanistic Study) What Protonated Imine??

S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131, 15358.

28

Activation of Hydrogen Cyanide --Strecker Reaction 2-4(Mechanistic Study) What Protonated Imine??

NH on urea was not exchanged to D.
D was observed on nitrogen in TM.

Urea didn't ptrotonate imine, i. e., to give
TM, the interaction between the urea
and the substrate was not necessary.

S. J. Zuend and E. N. Jacobsen, J. Am. Chem.
Soc. 2009, 131, 15358.

29

Activation of Hydrogen Cyanide --Strecker Reaction 2-5(Mechanistic Study) Enantioselectivity-Determining Step

S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc.
2009, 131, 15358.

Scheme 8. Catalyst-Controlled, HNC-Mediated Imine Hydrocyanation 30

Activation of Hydrogen Cyanide --Strecker Reaction 2-6(Mechanistic Study) Enanthioselectivity
Figure 13. Calculated transition structures for
HNC addition to imine 2a catalyzed by 6a.
Transition structures leading to the (A) majorand (B) minor enantiomer are shown.

There are no apparent “stericclashes” that might explain whysome transition structures are
significantly higher in energy
than the one leading to (R)-TMwith catalyst.

Why A is more stable than B ??

S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131, 15358.
31

Activation of Hydrogen Cyanide --Strecker Reaction 2-7(Mechanistic Study) Focus on the Distance between Catalysts and Cyanide Anion(S)-TS with 6c(S)-TS with 6a(R)-TS with 6a6a-h(in next slide)
Figure 15. H-bond distances between thiourea(X = S) or urea (X = O) and cyanide anion.

Smaller d1+d2 = More stable complex
Figure 16. Correlation of transition structure bondlength with enantioselectivity for HNC addition to imine
2a. Plot of the sum of the cyanide-(thio)urea H-bondThere was few difference of the sums
lengths in B3LYP/6-31G(d) transition structures versus(=d1+d2) between (S)-TS and (R)-TS .
experimental energy difference between (R)- and (S)transition states.
S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131, 15358.
32

Activation of Hydrogen Cyanide --Strecker Reaction 2-8Structures of 6a - h33

Activation of Hydrogen Cyanide --Strecker Reaction 2-9(Mechanistic Study) Focus on the Distance of Another Part of the Complex

6a-h

Figure 17. H-bond distances between catalyst andiminiumand between and cyanide anion and iminium.
Figure 18. Correlation of transition structure bond lengthwith enantioselectivity for HNC addition to imine 2a. Plotof the sum of the cyanide N-iminium H + amide Oiminium H bond lengths in B3LYP/6-31G(d) transition
structures versus experimental energy difference
between (R)- and (S)-transition structures.

The basis for enantioselectivity:
Degrees of iminium ion stabilization

S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131, 15358. 34

Contents
1. Introduction
Hydrogen bond
Organocatalyst
Urea/Thiourea
2. Organocatalysis
Pioneering Studies
Recognizing Carbonyl
Nitro Group
Sulfonate
Hydrogen Cyanide
3. Material
4. Bioactive compound
5. Summary35

Gelation using H-bond 1

3. Material

Structures and Gel/sol images
Compound(s) in MCH at elevated temperature .

Cooling to rt

Gel or sol ??

Fig. 1 Structure of the ESDA and the NDI derivatives.

Urea

Fig. 2 Gel/sol images.
Total concentration ineach case = 0.3 wt%.

ESDA-1+
NDI-PyESDA- 2+NDI-Py

ESDA-1

NDI-PyESDA : external structure
directing agent
NDI: naphthalene-diimide
MCH: methylcyclohexane

Only ESDA-1 and NDI-Py mixture lead to gelation.
For gelation, both the urea core and the π-conjugated chromophore ware needed.
S. Ghoust, et al, Chem. Comm. 2012, asap, DOI: 10.1039/c2cc36536g.

36Gelation using H-bond 2
Proposed model of gelation

3. Material
ESDA : external structure directing agent
NDI: naphthalene-diimide
MCH: methylcyclohexane

Fig. (a) Proposed model of gelation by H-bonded assembly of ESDA-1 + NDI-Py.

General characteristics of fibrillar gel:Superior abilities to transport of charge carriers.
Highly unpredictable photophysical properties.

S. Ghoust, et al, Chem. Comm. 2012,
asap, DOI: 10.1039/c2cc36536g.

37

Gelation using H-bond 3

3. Material

Experiment for Checking H-bond

N-C=O(urea)

N-C=O(urea)
NH(urea)NH(urea)

Fig. Selected region of the FT-IR spectrum of (a) ESDA-1 (0.5 wt %), (b) ESDA-1 + NDI-Py gel in MCH (1 wt%).

Frequency shift of NH and N-C=O to low energy(right) showed H-bond.
S. Ghoust, et al, Chem. Comm. 2012, asap, DOI: 10.1039/c2cc36536g.

38Gelation using H-bond 4

3. Material

Physical Properties –Molphologgy
ESDA-1 + NDI-Py

ESDA-2 + NDI-Py

Micrometer long fibers discontinuous spheres→Gel→no GelFig. AFM images.

ESDA-1 + NDI-Py:
H-bonding among the urea groups
and π-stacking among NDI-Py→ the 1D assembly is too rigid to fold
→ fibrillar morphology

ESDA-2 + NDI-Py:
π-stacking among NDI-Py alone→ spherical assemblies

S. Ghoust, et al, Chem. Comm. 2012, asap, DOI: 10.1039/c2cc36536g.
S. Ghoust , et al, Chem. Eur. J. 2012, 18, 9849.

39

Gelation using H-bond 5

3. Material

Physical Properties --Photoluminescence

Shift to longer wave length.

SolGelFig. Intensity normalized absorption (dashed line) and emission (solid line) spectra of gel (blue) and sol (black).
Concentration of each component in gel (MCH) and sol (CHCl3) state=2.0 mM and 0.025 mM, respectively for
UV/vis and PL experiments
S. Ghoust, et al, Chem. Comm. 2012, asap, DOI: 10.1039/c2cc36536g.
40
C. R. S. Moller, et al, Angew. Chem. Int. Ed. 2011, 50, 3376.

Gelation using H-bond 6

3. Material

Physical Properties --Electrical Conductivity (σ)

ESDA-1/NDI-Py gel had good electrical conductivity.
S. Ghoust, et al, Chem. Commun. 2012, asap, DOI: 10.1039/c2cc36536g.
41
S. I. Stupp , et al, Chem. Commun., 2011, 47, 5702.

Contents
1. Introduction
Hydrogen bond
Organocatalyst
Urea/Thiourea
2. Organocatalysis
Pioneering Studies
Recognizing Carbonyl
Nitro Group
Sulfonate
Hydrogen Cyanide
3. Material
4. Bioactive compound
5. Summary

42

Anticancer activity using H-bond 1

4. Bioactive compound

About Hedgehog (Hh) Signaling Pathway and Medulloblastomas(骨髄腫)

Medulloblastomas

Fig. 1 Components of the Hh signal pathway
and molecular sites targeted by Hh pathway
inhibitors.

K. M. Moslin, et al, ChemMedChem 2010, 5, 500.

43

Anticancer activity using H-bond 2

4. Bioactive compound

Smo inhibitors

Isolated from Veratrum grandiflorum
by T. Hasammune in 1964

• In clinical trials (Phase II)• Smo mutation and the resistance wasobserved in mice.

-(AcTU)-(AcU)-(AcG)
T. Hasammune, et al, Tetrahedron Lett. 1964, 16, 193.
M. Ruat , et al, Molecular Pharmacology 2010, 78, 658.
44
M. Ruat , et al, J. Med. Chem. 2012, 55, 1559.

Anticancer activity using H-bond 3

4. Bioactive compound

Proposed Fitting Model(AcTU)(AcG)

HBA: hydrogen bond acceptor groups
HY: hydrophobic regions

AcTU and AcG had the samephrmacophore as the compound
reported to be active as Smoinhibitor.
Fig. Compounds in two different conformations
layout (A,B) with the pharmacophoric model for
Smo antagonists. HBA features are constituted
by a smaller sphere accommodating thehydrogen bond acceptor group, by adirectionality vector represented by an arrow,and by a larger sphere intended to allocate thehydrogen bond donor group of the target
macromolecule.

K. M. Moslin, et al, ChemMedChem 2010, 5, 500.

45

Anticancer activity using H-bond 4

4. Bioactive compound

Involvement of H-bond

S < O < NH
Electronegativity

Scheme Proposed H-Bonding Network for the Three Bio-isosteric Structures AcTU, AcU, and AcG towards a Putative
Carboxylate Located on Smo (in Agreement with the Conformations of AcTU and AcG Shown in the previous slide).

46

Summary

5. Summary

1. Introduction
Hydrogen bondUrea has an ability to play important roles
Organocatalyst
in various areas.
Urea/Thiourea
2. Organocatalysis
Pioneering Studies
Recognizing Carbonyl
Nitro Group
Activation of substrates via oxygen atoms.
Sulfonate
Activation of substrates via theHydrogen Cyanide
ion different from the substrate.
3. Material
Activation of reagents via nitrogen atoms.
4. Bioactive compound
5. Summary
Urea for gel.
Urea for anti-cancer activity.
References「進化を続ける有機分子触媒」 化学同人 丸岡啓二 [編]「有機分子触媒の新展開」 シーエムシー出版 監修 柴崎正勝
E. N. Jacobsen, et al, Chem. Rev. 2007, 107, 5713.
S. J. Connon, SYNLETT 2009, 3, 354.

Thank you.

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