The Nature of the Hydrogen Bond and its Application Towards Enantioselective

Catalytic Reactions

Lead Material:Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.Pihko, P. M. Angew. Chem. Int. Ed. 2004, 43, 2062.Jeffrey, G. A.; Saenger, W. Hydrogen Bonding in Biological Structures, Springer-Verlalg, New York, 1991.

Jamie TuttleMacMillan Group

2/02/05

A brief introduction to various hydrogen bond applications

! Examples of hydrogen bonding are incredibly common

- Mineralogy, material science, organometallics, biochemistry, organic chemistry, supramolecular chemistry molecular medicine and pharmacy

! Many important structural functions

- Stabilizes protein folding, organizes DNA, organizes water and carbohydrates

N

NN

N

HN

N

N

O

O

H

H

A T

N

HN

NH

N

O

O

NH

O

HO

H

parallel protein beta sheets DNA

Garrett,R. H. and Grisham, C. M. Biochemistry, Harcourt Brace College, Orlando, 1995.

O

HO

H

HOH

H

HO

O

! Being discovered and elaborated on in bioorganic, organic and inorganic chemistries

HO

HOHO

H

H

OHHO

OH

H

carbohydrates

Saenger, J. W. Hydrogen Bonding in Biological Structures, Springer-Verlag, New York, 1991.

M X

N

H

HCl

Au

ClCl

Cl

N

Ph

Ph

H

Crabtree, R. H. et al. Inorg. Chem. 1995, 34, 3474.

H

Hydrogen bonds and reactivity

! Lewis acid activator

! Transition state organizer

O H+O O

NO O

NO

H HH

! Reaction lubricant

- Initially seen in enzymes and is now be utilized in current synthesis- Provide a route for asymmetric catalysis- Dual reactivity

- LUMO lowering catalysis

- Can provide a source of energy to facilitate a reaction- Completes a "circuit" to allow for reaction to occur

! The proposed interaction

- Charge transfer occurs from an electron lone pair from an acceptor (A) to the antibonding orbital of a donor (D) hydrogen bond

! " D#$#

The three major types of H bonds and important parameters

! General Characteristics

- The "normal" hydrogen could also be termed as the "weak strong" or "strong weak" H bond

interaction type

Strong Moderate Weak

bond lengths (A)H- - -A

lengthening of X–H (A)

X–H vs. H- - -A

X- - -A (A)

directionality

bond angles

bond energy (kcal/mol)

1H downfield shift

strongly covalent

mostly electrostatic

electrostatic/dispersed

1.2–1.5 1.5–2.2 2.2–3.3

0.08 – 0.25 0.02 – 2.2 >2.2

X–H ~ H- - -A X–H<H- - -A X–H << H- - -A

2.2–2.5 2.5–3.2 >3.2

strong moderate weak

170–180 >130 >90

15–40 4–15 <4

14–22 <14

°

°

°

(°)

Qualitative properties H bond lengths

! Strong hydrogen bonds

! Moderate hydrogen bonds

! Weak hydrogen bonds

X H Ad1 d1

d1 ~ d2

pKa X ~ pKa A

X H X H XX

X H X H XX

similarly

X H Ad1 d1

d1 < d2, X–H is long compared to weak bonds

X H Ad1 d1

d1 < d2, X–H is shorter than in moderate H bonds

O

H

H

H O

H

H

pKa ~ –1.7

O

O

R

H

O

O

R

pKa ~ 4.76

- C–H donor groups are most widely studied, includes the H-bond pi interaction- generally regarded as electrostatic/dispersed- ability to form bifurcated and trifurcated structures

- A reasonable way of thinking about the H-Bond is as a frozen proton transfer event- Currently no widely accepted theoretical method for predicting H bonds exists

Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.

O/N–H bonded species are 2–4 kcal/mol higher with neutralspecies and 15 kcal/mol higher in charged species

- moderate bonds have both weak and strong characteristics and tends to be blurred depending upon the experimental treatment- generally regarded as electrostatic

!+!"

The types of hydrogen bond geometries

! Two centered hydrogen bonds

! Three centered hydrogen bonds or bifurcated H bond

! Four centered hydrogen bonds or trifurcated H bond

X H A

X H

A

A

X H A

A

A

N

H

H

A3

A2

A1

- most understood and reasearched

- most examples are found in biology, especially carbohydrates (~25%) and amino acids (over 25%)

NH(CH2CH2OH)3N

H

O

OO=

H- - -O, 2.14–2.35 AN- - -O, 2.71–2.86A

- Rare, found in molecules that have a high density of donors and acceptors - Also found in biology

F H F

NH3H Bn

HOH OH

Hydrogen bond energies

Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.

! Energies for some gas phase dimers

F H F

H2O H OH2

H3N H NH3

OH H OH

H4N OH2

H4N Bn

HOH Cl

COOH OCOH

HOH OH2

NCH OH2

HOH Bn

F3C OH2

MeOH Bn

NH3 Bn

HCCH OH2

H2CCH2 OH

HSH H2S

CH4 FCH3

Dimer Energy (kcal/mol)

39

33

24

23

19

17

13.5

Dimer Energy (kcal/mol)

7.4

4.7–5.0

3.8

3.2

3.1

2.8

2.2

2.2

1.0

1.1

0.2

- strong H bonds, HOH- - -Cl is borderline

-moderate to weak hydrogen bonds

! Comparing to other covalent BDE

H2C CH2

Ph I

Et I

Me H

HO OH

t-BuO Ot-Bu

I I

BDE

171

105

65

53

BDE

51

38

36

- the strongest H bonds start to take on a covalent nature!

Donor/Acceptor Strengths

! Relative donor strengths

- General rule: donor strength is increased by neighboring electron-withdrawing groups and decreased by electron donating groups

O–H > N–H > S–H > C–H

oxygen subclass

H3O+ > O=C–OH > Ph–OH > Csp3–OH > H2O > OH–

nitrogen subclass

Im+N–H > R3N+–H > R2NH+–H > Csp2N–H > Csp3NH > N–NH2

carbon subclass

Cl3CH > C –H > (RN2)2Csp2 –H > (Cl, C)C–sp3 –H > R2C –H > R3C –H > O –CH3 >CH3CH2 –H

! Relative acceptor strengths

oxygen subclass

OH– > COO– > H2O > Csp3–OH >Ph–OH > C–NO2 > M–CO

nitrogen subclass

Csp3–NH2 > R2N–H > R3N–H > CN > Csp2NH2 > C=N–S

halogen subclass

F– > C–F > Cl– >Br– > I–

- General rule: acceptor strength is increased by neighboring electron-donating groups and decreased by electron donating groups withdrawing groups

Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.

- These trends are highly dependent on acceptor/donor pairings

Other interesting characteristics

! Cooperativity

!"X H A

!+ !"

X H!" !+

X H!" !+

Y H!" !+

- Charges flow through the X–H sigma bonds. The net result is an overall strengthening of both sigma bonds by ~ 20%- This effect drives the clustering of polar groups (e.g. carbohydrates)- Anticooperativity

! Donor directionality

- the main feature distinguishing a H bond from van der Waals interaction is its preference for linearity- degree of directionality depends on polarity of donor, O–H>C

! Acceptor directionality

H>C=CCH2>CH3

Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.

O S

- for stong hydrogen bonds, the direction is the same as if a hypothetical proton transfer reaction occurred

- rule of thumb: the electron density on oxygen and nitrogen are diffuse enough that linear geometries are favored

! Mixed strong/weak interactions

O H X HO H

O

F

OHOH

- difficult to assess structural importance

The CH ! " interaction– a weak hydrogen bond

! Intramolecular properties

Nishio, M. et al. The CH/# Interaction Evidence, Nature and Consequences, Wiley-VCH, Inc., New York, 1998.

H

H H

n(H2C) OH (CH2)nOH (CH3)n

n = 1,2 in most cases

OH

! Intermolecular properties

H

H H

H

H

stabilized 2–4 kcal/mol

acceptor substituent effects: NO2<Br<Cl<H~Et<Me<NH2donor substituent effects: CO,NMe,O, for C6H5CH2XCHMe2

O

H

H

O

H

H

H

HH

H

C

H

HH

H

acceptor substituent effects: Cl<D<CD3<p-(CD3)2<o-(CD3)2<(CD3)6 for C6H6-nXn/CHCl3 donor substituent effects: NO2<Br<Cl<H<Me<NH2 for C6H6/CH3C6H4Y

! Reactivity effects

C5H11

O

O R

OO

O

R = Me S:R 50:50 p-C6H5C6H4NH S:R 92:8

- remote functionalization reactions, diastereofacial and enantiofacial selectivity are all possible

O

RPh H

CH2

R' Ph

Mg

Cl

RPh

HO HR R' %ee

Me Me

t-Bu i-Pr

38

91

Corey, E. J. et al. J. Am. Chem. Soc. 1972, 94, 8616. Mosher, H. S. et al. J. Org. Chem. 1964, 29, 37.

The low barrier hydrogen bond in enzymes

! General characteristics

Cleland, W. W. et al. J. Bio. Chem. 1998, 273, 25529.

Cleland, W. W. Arch. Biochem. Biophy. 2000, 382, 1.

- basically the same as a strong hydrogen bond- enzymes modulate the pKa of a substrate to match that of the amino acid residue to which it is bonded

O H OO H O

O OH O OH

Ser195 O H NN H

O

O

Asp102

His57

! Chymotrypsin, a serine protease, and its weak hydrogen/LBHB catalytic cycle

Ser195 O H NN H

O

O

Asp102

His57O

NHRpeptidyl+ peptide

Ser195 O NN H

O

O

Asp102

His57O

NHRpeptidyl

H

– H2NR

Ser195 O NN H

O

O

Asp102

His57O

peptidyl

active site ground state compression event occurs

LBHB forms increases pKaimidizole

acylated system begins to reset

Long before round bottom flasks, enzymes roamed the earth

! Hydrogen bonded scaffold acts as cataytic site for protease activity

Northrop, D. B. Acc. Chem. Res. 2001, 34, 790.

Bachovchin, W. W. et al. Science 1997, 278, 1128.

O

O H O

O

HO

O

O H O

O

HO

O

O H O

O

HO

O

O H O

O

HO

O

O H O

O

HO

OH

O H O

O

1 2 3 4

5 6 7

O

RHN R O

RHN R O

RHN R

O

RHN R

O

R

N R

!"!" !" !"

!" !"

H H H

O

O H O

O O

O H O

O

HO

H

H

HO

H

H

- compounds 1–3 each contain low barrier hydrogen bond.- electron flow model theory- LBHB theory- Alzheimer #-secretase/HIV

+H2O

An example of enzyme mimicry–chemists are learning how to use H bonds

! A porphyrin-esque approach towards H2O2 activation

N

N N

N

MES

MES

Mn

MES

O

Me

Me

CO2H

t-Bu

t-Bu

catalyst

O0.2 mol% catalyst

25 eq. 1,5 dicyclohexylimidazole147 eq. H2O2

CH2Cl2, RT, 3h

70% yield

Nocera, D. G. et al. J. Am. Chem. Soc. 2003, 125, 1866.

t-Bu

Me

Me

t-Bu

Mn

O

OO

HH

t-Bu

Me

Me

t-Bu

Mn

O

O

OO

active speciesH bonded intermediateproton coupled electron transfer

- Control experiments indicate complex greatly increases rate of epoxidation- Did not completely rule out any free radical degradation pathways

A non-heme example of O2 activation

! The first reported example of an iron complex activation of molecular oxygen

Borovik, A. S.; Macbeth, C. E. et al. Science 2000, 289, 938.

FeN N

O

N

N

O

NMe

MeMe

ON

Me MeMe

HH

O

N Me

MeMe

H

III

NNH

NH

Me

O MeMe

3

1) KH (4 eq.) DMA, Ar, RT2) KH (3 eq.) DMA, Ar, RT3) Fe(OAc)2 DMA, Ar, RT4) O2 (0.5 eq.)5) H2O, RT

- Homolysis of the O2 bond creates the high spin Fe-oxo species- Produces a crystallizable-stable oxygen radical species, stabilized by hydrogen bonding- Compare this to similar cytochrome p450 species that oxidize C-H bonds via similar intermediates

Hine and co-workers develop the first hydrogen bond activated reaction

O O

Hine, J.; Ahn, K. J. Org. Chem. 1987, 52, 2083.Hine, J. et al. ibid. 1985, 50, 5096.

O

O

NO

Me

Me

Me

H

H

! The initial idea was based on stable hydrogen bonded crystal structures

PO

N

N

NMeMe

Me

Me

Me Me

OO

Me

Me

- A comparison of 1,8 biphenylenediol (pKa = 8.01) to m-nitrophenol (pKa = 8.36) indicated the diol bound 50 x's stronger.

! Rate studies provide convincing proof of a stable hydrogen bond catalyst

Et2NHO

OH

NEt

Et

butanone

aromatic alcoholcatalyst

phenolp-Cl-phenolm-Cl-phenol

m-nitrophenolp-cyanophenolp-nitrophenol

catechol1-biphenylenol

8-methoxy-1-biphenylenol1,8-biphenylenediol

105kc, M-2s-1 pKa

6.07.78.214.315.317.011.911.57.375

9.999.419.128.367.977.159.368.649.158.01

- The only yield reaction was set-up using 57 mol% catalyst and provided the product, after 15 days at 35 °C, in 86% yield.

- The aryl groups of both donor and acceptor are planar.

- used 3.75 eq. catalyst

Application of Hine's discovery

! Kelly catalyzes the Diels Alder reaction

Kelly, T. R. et al. Tet. Lett. 1990, 31, 3381.

n-Pr n-Pr

NO2NO2

CHCl3, 10 min. RTMe

O

COCH3

90% (3% bgd.)

- Other dienes: 2,3-dimethylbutadiene, 1-methoxybutadiene

- Other dienophiles: acrolein, 2-methylacrolein, 3-methylacrolein, 3-phenyl acrolein, methylacrylate

OH OH

- Esters and methoxydienes work poorly.

n-Pr n-Pr

NO2NO2

O OO

O

R

Me

H HOMe

- The methoxy substituent competes with aldehydes for H bonding

10 eq. 1 eq.

(0.4–0.5 mol eq.)

Another conceptual step leads to a hydrogen bonding framework

! A purely crystallographic analysis of urea scaffold/carbonyl structures

Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 5896.

NH

NH

O

X Y

ZXNO2CF3NO2NO2

YNO2CF3HH

ZHHHNO2

- Finds that ortho EWG's have most prominent effect and may induce aryl–H/CO bonding.

Etter, M. C. Acc. Chem. Res. 1990, 23, 120.

! A set of rules for predicting H-bond in various molecules is proposed

Some more interesting facets:- Six membered intramolecular H bond structures are preferred over intermolecular bonding.- After six membered ring bonding, the remaining H donating/accepting groups interact.- 2-aminopyrimidine as an illustrative example.

N N N N

N NH H H H

H

(1) (1)

(4)

(2) (3)

O

O

R

N1 > N2 > acid carbonyl > N3 = N4proton accepting ability

(a) (a)(b) (c)

proton donating abilityOH (acid) > Ha > Hb > Hc

! Free radical allylation

Curran, D. P.; Kuo L. H. J. Org. Chem., 1994, 59, 3259.

NH

NH

O

CF3 CF3

CO2C8H17C8H17O2C

HNS

O

SePh

O

NH

S

O

NH

ArNH

Ar

O

top face shielded

Two mechanistically different reactions, same H bond manifold

Curran, D. P.; Kuo, L. H. Tet. Lett. 1995, 36, 6647

SnBu

AIBN, benzene, 55 °C, 24 h

HNS

O

O

1

eq. 10.250.51.0

trans/cis7.1:111.3:114.1:1

yield707272

! Kinetic studies indicate H bonding accelerates the Claisen rearrangement

O

OMe

E:Z = 2.6:1

1

benzene, 80 °C

O

R

catalyst1

1

1

1

thioureaDMSO

DMSO + 1

eq.0

0.10.41.01.0

5 eq.5eq, 1eq

krel

12.75.022.43-41.91.3

O

(1.25 eq.)

! Parallel library generated catalysts to effect the Strecker reaction were screened to provide the

thiourea scaffold

Jacobsen develops the most efficient and broadly used scaffold to date

Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407. (for some examples of thiourea catalyzed Diels Alder reactions)

Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279. (for substrate scope)

PhHN

NH

NH

O

S

N

HO

t-Bu

OMe

MeMeMe

N

R H

(2 mol%)

toluene, – 78 °C, 24 hTFAA workup

HCN (2 eq.)R

N

CN

O

F3C

RPh

p-OCH3C6H4p-BrC6H42-naphthyl

t-butylc-hexyl

yield (%)789265887077

ee (%)917086888583

- The original goal of the catalyst screen was to incorporate metal binding sites on the scaffold.- Jacobsen, "a sequence of nonobvious modifications in the catalyst structure."

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

Origins of selectivity in the catalyzed Strecker reaction

! NMR solution structure and MOLMOL modelling lead to a set of selection rules

N

HO

Me

Me

O

O Me

Me

Me

HN

O

HN

O

HN

N

Ph

Me

=

Me

- Determined that only the Z-isomer binds the catalyst and is bridged by the urea nitrogens.- Large groups are directed into solvent.- The small group is placed directly into the catalyst.- The N-substituent is directed away from the catalyst.

! Synthesis of B-aryl, B-amino acids via asymmetric Mannich reactions

Jacobsen extends this technology towards other transformations

N

H R

Boc OTBS

OiPr

Ph NNH

NH

O

S

N

HO

t-Bu

MeMeMe

Me

Me

Me

Me(5 mol%)

PrOi R

O NHBoctoluene, 48 h, – 40 to 4 °C

1)

2) TFA, 1 min.

- Tolerates a wide range of aryl groups, no aliphatic examples.- Currently the mechanism is not well understood

Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.

! Nitro-Mannich reaction

Yoon, T. P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2005, 44, 466.

Me2NNH

NH

O

SMeMe

Me

NHAcNH

Ph

NO2R1

R2

1 eq. 5 eq.

1 eq. 2 eq.

i-Pr2NEt, toluene4 A mol. sieves

(10 mol%)

PhNO2

NHBoc

R1 R2

%ee: 86-98%yield: 84-99

- Only aryl aldimines are used for the transformation- Suspect the catalysts may activate BOTH reactants.

>5:1 syn: anti d.r in most cases>92% ee in all cases>90% yield in most cases

! Takemoto develops the Michael reaction of malonates and nitroolefins

Other carbon-carbon bond forming reactions catalyzed by the thiourea scaffold

NO2

HN

HNF3C

CF3

S

NMe2

NO2

EtO2C CO2Et

(0.1 eq)

EtO2C CO2Et

toluene, rt, 24 h 86% yield93% ee

Takemoto, Y. et al. J. Am. Chem. Soc. 2003, 125, 12672.

- aromatic olefins give the best yields and ee in most cases.- aliphatic olefins give decent yields but lower ee. (81% ee in both examples)

! Another variant of the Mannich reaction

N

Ar

P(O)Ph2(0.1 eq.) catalyst above

RCH2NO2 (10 eq.)

(2 eq.)

CH2Cl2, rt

Takemoto, Y. et al. Org. Lett. 2004, 6, 625.

ArNO2

HNP(O)Ph2

yields ranged from 57–87%ee's ranged 63–76% ee

NH

NH

S

N

NO O

NH

NH

S

NMeH

NO O

RH

HR H

Me

! Preparation of imines

One well known and one not-so-well-known H bond reaction

Crabtree, R. H. et al. Chem. Commun., 1999, 2109.

O

NH2Bn

O2S SO2

NH2NH2

1 eq. 11 eq.

NBn

CH2Cl2, –20 °C

MgSO4 anh.

- Only rate of catalyst acceleration was probed.

! Rawal's TADDOL catalyzed Diels Alder cycloaddition

Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 1124, 9662.Rawal, V. H. et al. PNAS, 2004, 101, 5846.

NMe2

TBSO

OH

OH

NaphNaph

NaphNaph

O

OMe

Me

toluene, –78 °C or –40 °C O

TBSO

N

R

Me Me

AcCltoluene/CH2Cl2–78 °C, 15 min.

O

O R

O

O O

OH

CHOMe

H O

(20 mol%)

(2 eq.)

Chiral Bronsted Acid Catalysis! Mannich type reaction

HO

N

PhMe

H

OTMS

OEt

PhNO2

PhNO2

O

OP

OH

O

Akiyama, T. et al. Angew. Chem. Int. 2004, 43, 1566.

PhCO2Et

HN

Me

HO

syn/anti 87:1396% ee (syn)100% yield

1.0 eq. 1.5 eq.

10 mol%

10 more examples

- Only aromatic aldimines are used- All the yields were high, as was syn/anti selectivity.- ee's ranged from 81% – 96%

O

OP

O

O

NO2

NO2

Ar

NH Ar

O

HR

O

OH

OH

Schaus, S. E.; McDougal, N. T. J. Am. Chem. Soc. 2003, 125, 12094.

R

R

CF3

CF3

! Morita-Baylis-Hillman reaction

OHB

R3P

OOH

R

(2 mol%)

Et3P (0.5 eq)THF, –10 °C, 48 h, Ar1 eq. 1 eq.

R =

R = aliphatic, 82 – 96% ee 70 – 88% ee R = conjugated, 67, 81% ee low yields

Chiral Bronsted Acid Catalysis

! Aza Henry reaction

Johnston, J. N. et al. J. Am. Chem. Soc. 2004, 126, 3418.

HN HN

N NH

NH

R1C6H4

NO2

R2

R1C6H4

NO2

HN

R2

BOC

10 mol%

neat, –20 °C

- Syn preferred of anti- Yields range from 51 – 69 %- mechanism unclear

OTf

(4.8 eq)

Conclusions

- The hydrogen bond is a fascinating molecule whose theory of interaction needs further development

- A well of chemical reactivity is filled with possibilities

- Theory is not as important as practice

- May be able to exploit a wide range of interactions to develop an asymmetric, catalytic system