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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