Download The Nature of the Hydrogen Bond and its Application Towards

The Nature of the Hydrogen Bond and its
Application Towards Enantioselective
Catalytic Reactions
Jamie Tuttle
MacMillan Group
2/02/05
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.
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
HO
O
H
H O
H
H
N
OH
H
H
O
H
H
N
H
H
OH
HO
HO
O
H
OH
O
N
H
carbohydrates
N
H
O
O
HO
HN
N
H
H
N
N
N
O
H
O
N
N
N
A
O
parallel protein beta sheets
T
DNA
! Being discovered and elaborated on in bioorganic, organic and inorganic chemistries
N
H
M
X
H
Ph
Cl
Cl
Au
Cl
H
N
Cl
Ph
Crabtree, R. H. et al. Inorg. Chem. 1995, 34, 3474.
Saenger, J. W. Hydrogen Bonding in Biological Structures, Springer-Verlag, New York, 1991.
Garrett,R. H. and Grisham, C. M. Biochemistry, Harcourt Brace College, Orlando, 1995.
Hydrogen bonds and reactivity
! 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
! Lewis acid activator
O
H+
H
H
O
O
N
O
- LUMO lowering catalysis
! Transition state organizer
- Initially seen in enzymes and is now be utilized in current synthesis
- Provide a route for asymmetric catalysis
- Dual reactivity
! Reaction lubricant
- Can provide a source of energy to facilitate a reaction
- Completes a "circuit" to allow for reaction to occur
O
H
N
O
The three major types of H bonds and important parameters
! General Characteristics
Strong
Moderate
Weak
interaction type
strongly
covalent
mostly
electrostatic
electrostatic/
dispersed
°
bond lengths (A)
H- - -A
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
14–22
<14
15–40
4–15
°
lengthening of X–H (A)
X–H vs. H- - -A
°
X- - -A (A)
directionality
bond angles (°)
1H
downfield shift
bond energy (kcal/mol)
<4
- The "normal" hydrogen could also be termed as the "weak strong" or "strong weak" H bond
Qualitative properties H bond lengths
! Strong hydrogen bonds
O
X
d1
H
d1
X
H
A
d1 ~ d2
X
X
H
X
similarly
X
H
X
H
O
X
pKa X ~ pKa A
H
X
R
H
H
H
O
O
H
H
O
R
O
pKa ~ –1.7
pKa ~ 4.76
! Moderate hydrogen bonds
X
d1
H
d1
A
d1 < d2, X–H is long compared to
weak bonds
- moderate bonds have both weak and strong characteristics and
tends to be blurred depending upon the experimental treatment
- generally regarded as electrostatic
! Weak hydrogen bonds
- 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
O/N–H bonded species are
!" d1
d1 !+
2–4 kcal/mol higher with neutral
X
H
A
species and 15 kcal/mol higher
in charged species
d1 < d2, X–H is shorter than in moderate H bonds
- 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.
The types of hydrogen bond geometries
! Two centered hydrogen bonds
- most understood and reasearched
F
X
H
A
H
F
NH3H
Bn
HOH
OH
! Three centered hydrogen bonds or bifurcated H bond
- most examples are found in biology, especially carbohydrates (~25%) and amino acids (over 25%)
A1
A
X
H
H
A2
N
A
H
A3
! Four centered hydrogen bonds or trifurcated H bond
- Rare, found in molecules that have a high density of donors and acceptors
- Also found in biology
A
X
H
A
A
O
NH(CH2CH2OH)3
=
O
H
N
O
H- - -O, 2.14–2.35 A
N- - -O, 2.71–2.86A
Hydrogen bond energies
! Energies for some gas phase dimers
Dimer
F
H
Energy (kcal/mol)
F
Energy (kcal/mol)
Dimer
39
COOH
OCOH
7.4
H2O
H
OH2
33
HOH
OH2
4.7–5.0
H3N
H
NH3
24
NCH
OH2
3.8
OH
23
HOH
Bn
3.2
H4N
OH2
19
F3C
OH2
3.1
H4N
Bn
17
MeOH
HOH
Cl
13.5
OH
H
NH3
Bn
HSH
- strong H bonds, HOH- - -Cl is
borderline
H2CCH2
CH4
2.2
Bn
HCCH
2.8
OH2
2.2
1.0
H2S
OH
FCH3
1.1
0.2
-moderate to weak hydrogen bonds
! Comparing to other covalent BDE
H2C
CH2
Me
H
Ph
I
Et
I
BDE
171
105
65
53
BDE
HO OH
51
t-BuO Ot-Bu 38
I
I
36
- the strongest H bonds start to take on a covalent nature!
Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.
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
- General rule: acceptor strength is increased by neighboring electron-donating groups and decreased by electron
withdrawing groups
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–
- These trends are highly dependent on acceptor/donor pairings
Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.
Other interesting characteristics
! Cooperativity
!" !+ !"
!" !+
X
X
H
H
!" !+ !" !+
Y
A
H
X
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
H >C=CCH2>CH3
! Acceptor directionality
- for stong hydrogen bonds, the direction is the same as if a hypothetical proton transfer reaction occurred
O
S
- rule of thumb: the electron density on oxygen and nitrogen are diffuse enough that linear geometries are favored
! Mixed strong/weak interactions
OH
OH
O
H
X
O
H
O
H
F
- difficult to assess structural importance
Steiner, T. Angew. Chem. Int. Ed. 2002, 41, 48.
The CH ! " interaction– a weak hydrogen bond
! Intermolecular properties
O
H
H
C
H
H
H
O
H
H
H
H
H
H
H
H
H
H
H
H
Cl<D<CD3<p-(CD3)2<o-(CD3)2<(CD3)6
acceptor substituent effects:
for C6H6-nXn/CHCl3
donor substituent effects: NO2<Br<Cl<H<Me<NH2 for C6H6/CH3C6H4Y
stabilized 2–4 kcal/mol
! Intramolecular properties
H
H
H
n(H2C)
(CH3)n OH
(CH2)n OH
OH
n = 1,2 in most cases
acceptor substituent effects: NO2<Br<Cl<H~Et<Me<NH2
donor substituent effects: CO,NMe,O, for C6H5CH2XCHMe2
! Reactivity effects
O
O
O
Cl
Mg
C5H11
O
R
CH2
O
O
R = Me S:R 50:50
p-C6H5C6H4NH S:R 92:8
Corey, E. J. et al. J. Am. Chem. Soc. 1972, 94, 8616.
Ph
R
H
R'
HO
H
Ph
R
R
R'
%ee
Me Me
t-Bu i-Pr
38
91
Ph
Mosher, H. S. et al. J. Org. Chem. 1964, 29, 37.
- remote functionalization reactions, diastereofacial and enantiofacial selectivity are all possible
Nishio, M. et al. The CH/# Interaction Evidence, Nature and Consequences, Wiley-VCH, Inc., New York, 1998.
The low barrier hydrogen bond in enzymes
! General characteristics
- 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
O
H
H
O
O
O
H
O
O
H
O
! Chymotrypsin, a serine protease, and its weak hydrogen/LBHB catalytic cycle
His57
O
O
Asp102
Ser195 O
N
H
N
H
+ peptide
O
His57
peptidyl
Ser195 O
H
N
H
N
N
H
O
compression event occurs
O
Asp102
N
Asp102
His57
O
NHR
O
NHR
Ser195 O H
active site ground state
O
peptidyl
His57
O
LBHB forms increases pKa
imidizole
– H2NR
O
Asp102
peptidyl
Ser195 O
N
N
H
O
acylated system begins to reset
Cleland, W. W. et al. J. Bio. Chem. 1998, 273, 25529.
Cleland, W. W. Arch. Biochem. Biophy. 2000, 382, 1.
Long before round bottom flasks, enzymes roamed the earth
! Hydrogen bonded scaffold acts as cataytic site for protease activity
R
O
O
H
H
O
H
O
O
2
R
R
R
R
O
O
!"
!"
H
3
H
5
O
N
H
O
O
O
O
!"
H
O
4
R
H
O
OH
O
R
H
O
O
H
N
O
H
H
O
O
H
O
O
O
O
H
O
H
!"
H
N
H
O
O
H
N
O
H
O
1
R
O
R
O
H
O
O
R
H
N
O
H
O
O
6
O
O
H
7
O
+H2O
H
H
O
O
O
!"
H
O
!"
- compounds 1–3 each contain low barrier hydrogen bond.
- electron flow model theory
- LBHB theory
- Alzheimer #-secretase/HIV
Bachovchin, W. W. et al. Science 1997, 278, 1128.
Northrop, D. B. Acc. Chem. Res. 2001, 34, 790.
An example of enzyme mimicry–chemists are learning how to use H bonds
! A porphyrin-esque approach towards H2O2 activation
t-Bu
MES
CO2H
0.2 mol% catalyst
25 eq. 1,5 dicyclohexylimidazole
147 eq. H2O2
Me
O
O
N
Me
N
Mn
CH2Cl2, RT, 3h
N
N
70% yield
MES
t-Bu
MES
catalyst
t-Bu
t-Bu
O
O
Me
O
H O
H
O
Me
t-Bu
Mn
H bonded intermediate
proton coupled electron transfer
Me
O
O
Me
t-Bu
Mn
active species
- Control experiments indicate complex greatly increases rate of epoxidation
- Did not completely rule out any free radical degradation pathways
Nocera, D. G. et al. J. Am. Chem. Soc. 2003, 125, 1866.
A non-heme example of O2 activation
! The first reported example of an iron complex activation of molecular oxygen
O
N
N
H
Me
N
H
1) KH (4 eq.)
DMA, Ar, RT
2) KH (3 eq.)
DMA, Ar, RT
3) Fe(OAc)2
DMA, Ar, RT
4) O2 (0.5 eq.)
5) H2O, RT
Me
Me
3
Me Me
Me
O
H
H
Me
N
O
Me
N
Me Me
N
O
Me
HN
III
N Fe N
N
Me
O
- 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
Borovik, A. S.; Macbeth, C. E. et al. Science 2000, 289, 938.
Hine and co-workers develop the first hydrogen bond activated reaction
! The initial idea was based on stable hydrogen bonded crystal structures
O
Me
Me
H
O
N
Me
O
H
O
Me
Me
N
Me
Me
P
N
N
Me
Me
Me
O
O
Me
- The aryl groups of both donor and acceptor are planar.
- 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
O
O
aromatic alcohol
Et2NH
butanone
catalyst
OH
O
- The only yield reaction was set-up using 57 mol%
catalyst and provided the product, after 15 days at 35 °C,
in 86% yield.
Et
105kc, M-2s-1
phenol
6.0
7.7
p-Cl-phenol
Et
8.2
m-Cl-phenol
14.3
m-nitrophenol
15.3
p-cyanophenol
17.0
p-nitrophenol
11.9
catechol
11.5
1-biphenylenol
8-methoxy-1-biphenylenol 7.3
75
1,8-biphenylenediol
- used 3.75 eq. catalyst
N
pKa
9.99
9.41
9.12
8.36
7.97
7.15
9.36
8.64
9.15
8.01
Hine, J.; Ahn, K. J. Org. Chem. 1987, 52, 2083.
Hine, J. et al. ibid. 1985, 50, 5096.
Application of Hine's discovery
! Kelly catalyzes the Diels Alder reaction
OH
OH
n-Pr
n-Pr
(0.4–0.5 mol eq.)
O
NO2
Me
10 eq.
NO2
CHCl3, 10 min. RT
COCH3
1 eq.
90% (3% bgd.)
- Other dienes: 2,3-dimethylbutadiene, 1-methoxybutadiene
- Other dienophiles: acrolein, 2-methylacrolein, 3-methylacrolein, 3-phenyl acrolein, methylacrylate
- Esters and methoxydienes work poorly.
R
Me
OMe
O
O H
O
HO
n-Pr
- The methoxy substituent competes
with aldehydes for H bonding
n-Pr
NO2
NO2
Kelly, T. R. et al. Tet. Lett. 1990, 31, 3381.
Another conceptual step leads to a hydrogen bonding framework
! A purely crystallographic analysis of urea scaffold/carbonyl structures
X
Y
N
H
X
NO2
CF3
NO2
NO2
Z
O
N
H
Y
NO2
CF3
H
H
Z
H
H
H
NO2
- Finds that ortho EWG's have most
prominent effect and may induce
aryl–H/CO bonding.
Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 5896.
! 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.
(b) (c) O
R
(a) H (4) H (a)
H
H
N
(1) N
N
N
(1)
proton accepting ability
N1 > N2 > acid carbonyl > N3 = N4
(2) N
N
H
O
(3)
proton donating ability
OH (acid) > Ha > Hb > Hc
Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
Two mechanistically different reactions, same H bond manifold
! Free radical allylation
CF3
CF3
O
C8H17O2C
O
S
HN
SePh
N
H
Ar
1
O
N
H
SnBu
CO2C8H17
O
N
H
AIBN, benzene, 55 °C, 24 h
O
N
H
O
N
H
Ar
O
S
S
HN
top face shielded
(1.25 eq.)
O
eq. 1
0.25
0.5
1.0
trans/cis
7.1:1
11.3:1
14.1:1
yield
70
72
72
Curran, D. P.; Kuo L. H. J. Org. Chem., 1994, 59, 3259.
! Kinetic studies indicate H bonding accelerates the Claisen rearrangement
O
OMe
E:Z = 2.6:1
1
benzene, 80 °C
O
R
catalyst
1
1
1
1
thiourea
DMSO
DMSO + 1
eq.
0
0.1
0.4
1.0
1.0
5 eq.
5eq, 1eq
krel
1
2.7
5.0
22.4
3-4
1.9
1.3
Curran, D. P.; Kuo, L. H. Tet. Lett. 1995, 36, 6647
Jacobsen develops the most efficient and broadly used scaffold to date
! Parallel library generated catalysts to effect the Strecker reaction were screened to provide the
thiourea scaffold
Me
Ph
H
N
O
Me
Me
N
H
S
N
H
(2 mol%)
N
HO
OMe
O
N
HCN (2 eq.)
R
toluene, – 78 °C, 24 h
TFAA workup
t-Bu
F3C
R
H
- 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."
N
R
Ph
p-OCH3C6H4
p-BrC6H4
2-naphthyl
t-butyl
c-hexyl
CN
yield (%)
78
92
65
88
70
77
ee (%)
91
70
86
88
85
83
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)
Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407. (for some examples of thiourea catalyzed Diels
Alder reactions)
Origins of selectivity in the catalyzed Strecker reaction
! NMR solution structure and MOLMOL modelling lead to a set of selection rules
Ph
Me
N
H
N
H
N
HN
N
O
O
HO
O
Me
=
Me
Me
O
Me
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.
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
Jacobsen extends this technology towards other transformations
! Synthesis of B-aryl, B-amino acids via asymmetric Mannich reactions
1)
Me
Me
Ph
Me
N
Me
N
H
O
S
N
H
N
Me
HO
(5 mol%)
Boc
H
R
1 eq.
Me
t-Bu
OTBS
N
Me
O
toluene, 48 h, – 40 to 4 °C
2) TFA, 1 min.
OiPr
PrOi
R
%ee: 86-98
%yield: 84-99
- Tolerates a wide range of aryl groups, no aliphatic examples.
- Currently the mechanism is not well understood
2 eq.
NHBoc
Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
! Nitro-Mannich reaction
Me
Me2N
NH
Ph
1 eq.
R1
NO2
R2
5 eq.
O
Me
Me
N
H
S
N
H
(10 mol%)
NHAc
i-Pr2NEt, toluene
4 A mol. sieves
- Only aryl aldimines are used for the transformation
- Suspect the catalysts may activate BOTH reactants.
NHBoc
NO2
Ph
R1
R2
>5:1 syn: anti d.r in most cases
>92% ee in all cases
>90% yield in most cases
Yoon, T. P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2005, 44, 466.
Other carbon-carbon bond forming reactions catalyzed by the thiourea scaffold
! Takemoto develops the Michael reaction of malonates and nitroolefins
H
N
F3C
H
N
NMe2
S
NO2
CF3
EtO2C
(0.1 eq)
NO2
(2 eq.)
toluene, rt, 24 h
EtO2C
CO2Et
CO2Et
86% yield
93% ee
- aromatic olefins give the best yields and ee in most cases.
- aliphatic olefins give decent yields but lower ee. (81% ee in both examples)
Takemoto, Y. et al. J. Am. Chem. Soc. 2003, 125, 12672.
! Another variant of the Mannich reaction
N
(0.1 eq.) catalyst above
RCH2NO2 (10 eq.)
P(O)Ph2
CH2Cl2, rt
Ar
HN
yields ranged from 57–87%
ee's ranged 63–76% ee
S
N
H
N
H
O
O
R
NO2
Ar
S
N
P(O)Ph2
H
N
H
N
H
O
O
N
R
N
H
N
Me
Me
H
H
Takemoto, Y. et al. Org. Lett. 2004, 6, 625.
One well known and one not-so-well-known H bond reaction
! Rawal's TADDOL catalyzed Diels Alder cycloaddition
Me
Me
TBSO
Me
CHO
Naph
O
O
Naph
Naph
OH
(20 mol%)
OH
TBSO
Naph
R
O
toluene, –78 °C or –40 °C
NMe2
Me
N
AcCl
toluene/CH2Cl2
–78 °C, 15 min.
O
R
O
Me
(2 eq.)
O
O
O
H O
H
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 1124, 9662.
Rawal, V. H. et al. PNAS, 2004, 101, 5846.
! Preparation of imines
O2S
NH2
O
NH2Bn
1 eq.
O
SO2
NH2
CH2Cl2, –20 °C
MgSO4 anh.
N
Bn
11 eq.
- Only rate of catalyst acceleration was probed.
Crabtree, R. H. et al. Chem. Commun., 1999, 2109.
! Mannich type reaction
Chiral Bronsted Acid Catalysis
PhNO2
NO2
O
O
HO
O
HO
P
OH
OTMS
H
N
OEt
HN
PhNO2
10 mol%
Ph
Me
Ph
O
O
N
Ar
O
Ar
syn/anti 87:13
96% ee (syn)
100% yield
10 more examples
H
P
Me
1.5 eq.
1.0 eq.
O
CO2Et
NO2
- Only aromatic aldimines are used
- All the yields were high, as was syn/anti selectivity.
- ee's ranged from 81% – 96%
Akiyama, T. et al. Angew. Chem. Int. 2004, 43, 1566.
! Morita-Baylis-Hillman reaction
R
OH
OH
O
O
R
O
HB
OH
(2 mol%)
R
H
1 eq.
1 eq.
Et3P (0.5 eq)
THF, –10 °C, 48 h, Ar
CF3
R=
CF3
O
R
R3P
R = aliphatic, 82 – 96% ee
70 – 88% ee
R = conjugated, 67, 81% ee
low yields
Schaus, S. E.; McDougal, N. T. J. Am. Chem. Soc. 2003, 125, 12094.
Chiral Bronsted Acid Catalysis
! Aza Henry reaction
OTf
HN
N
HN
H
N
HN
NH
R1C6H4
NO2
R2
10 mol%
neat, –20 °C
BOC
NO2
R1C6H4
R2
(4.8 eq)
- Syn preferred of anti
- Yields range from 51 – 69 %
- mechanism unclear
Johnston, J. N. et al. J. Am. Chem. Soc. 2004, 126, 3418.
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