In Partial Fulfillment of the Requirements for the Degree of

Finally, I would like to thank all the members of the group with whom I have overlapped over the years for their (countless) helpful conversations, words of encouragement and time and energy, always freely given. Effects of the cyclometallic NHC ligand on catalyst activity and selectivity in various cross-metathesis assays, as well as macrocyclic ring-closing metathesis and other industrially relevant transformations, are investigated.

Mechanism of olefin metathesis

General schemes for common metathesis reactions

Therefore, much effort has been devoted to finding metathesis catalysts that exhibit kinetic selectivity for the formation of Z-olefins. Development of Z-selective ruthenium metathesis catalysts An original strategy for the design of Z-selective ruthenium alkylidenes.

Development of Z-Selective Ruthenium Metathesis Catalysts Original Strategy for the Design of Z-Selective Ruthenium Alkylidenes

Mechanism of carboxylate-driven C–H bond insertion to form catalyst 1.3

In the obtained cyclometalated catalyst 1.5, however, the C–H activated substituent was not the N-mesityl group, as expected, but the N-adamantyl group. Interestingly, the new cyclometal catalyst 1.5 was found to be highly Z-selective (91% Z) in the CM of allylbenzene and cis-1,4-diacetoxybutene.

Figure 1.1. Comparison of the proposed steric and electronic interactions for side- and bottom-bound ruthenacycles

Origins of Z-selectivity in cyclometalated ruthenium metathesis catalysts

Of the newly synthesized derivatives, nitrate-substituted catalyst 1.9 was found to perform best, catalyzing a variety of CM reactions with nearly 1000 turnover and ca. Computational data suggested that further increasing the bulk of the ortho substituents on the N-aryl group could lead to increased Z-selectivity.

Figure 1.2. Cyclometalated ruthenium metathesis catalysts 1.10–1.12. Mes = 2,4,6- 2,4,6-trimethylphenyl

This derivative and other new catalytically active species were synthesized using an improved method using sodium carboxylates to promote salt metathesis and C–H activation of these cyclometalated complexes. All of these new ruthenium-based catalysts were highly Z-selective in the homodimerization of terminal olefins.

Introduction

Prior to the work described in this chapter, nitrato-catalyst 2.3 was the best Z-z-selective ruthenium-based metathesis catalyst, with turnover number (TON) approaching 1000 and Z-selectivity averaging about 90%. Inspired by the computational data, we hypothesized that increasing the steric bulk of the N-aryl group of 2.3 would further destabilize the selective transition state E, thus increasing the Z selectivity.4 However, as mentioned in Chapter 1, efforts of previous to make significant changes in the NHC substituents, both in the cyclometalated group and in the N-aryl group, generally resulted in decomposition upon exposure to AgOPiv.5 To access stable cyclometalated species with various modifications to the substituents NHC, we sought to develop a gentler approach to forming this ruthenium-carbon bond.

Results and Discussion

Synthesis of pheromone 2.17 using catalyst 2.9

We next evaluated catalyst 2.9 in macrocyclic ring-closing metathesis (mRCM).9 Although Z-selective W- and Mo-based systems exhibit Z-selectivities as high as 97% for mRCM reactions, 10,11-catalyst 2.3 gives only ca. We were thus pleased to find that when dienes 2.18a-2.20a were exposed to catalyst 2.9, the macrocycles 2.18-2.20 were all obtained in modest yields and with only trace amounts of the E isomer evident by 1H and 13C NMR spectroscopy (table) 2.4).

Conclusions and Future Outlook

Since this paper was published in 2013 in the Journal of the American Chemical Society, catalyst 2.9 has been extensively studied in a variety of transformations. Carbon-13 NMR Spectroscopy: High-Resolution Methods and Applications in Organic Chemistry and Biochemistry, 3rd Edition; Wiley-VCH: and Applications in Organic Chemistry and Biochemistry, 3rd Edition; Wiley-VCH:.

Supporting Information

High-resolution mass spectra (HRMS) were provided by the California Institute of Technology Mass Spectrometry Facility using a JEOL JMS-600H high-resolution mass spectrometer. After cooling to room temperature, the mixture was filtered through celite, washed with CH 2 Cl 2 , and the filtrate was concentrated to a white powder.

Preparation of 2.22: A two-neck 100 mL RB flask equipped with a condenser was dried

The precipitated solids were filtered and washed well with warm hexanes and pentane to give g, 89%) as a green powder.

Preparation of 2.26: Bromoacetyl chloride (2.8 mL, 34 mmol) was added dropwise to a

The resulting residue was taken up in CH2Cl2, filtered over a pad of celite and concentrated. After stirring for 3 hours, the mixture is concentrated, taken up in CH2Cl2, filtered over a pad of celite and concentrated again.

General Procedure for Homodimerization Reactions: In a glovebox, a 4 mL vial was

Of the cyclometalated systems surveyed, most produced highly cis, syndiotactic polymers (>95% in many cases). To further verify the syndiotactic nature of the norbornene- and norbornadiene-based polymers produced by catalysts 3.1–3.3 , we turned to the chiral monomer 3.7 .

Figure 2.2. 1 H NMR (400 MHz, C 6 D 6 ) spectrum of 2.7.

Finally, we investigated the degree of head-to-tail (HT) selectivity exhibited by catalysts 3.1, 3.4, and 3.9 in the polymerization of racemic, asymmetrically substituted norbornenes. HT bias is measured by determining the ratios of head-head/head-tail (HH/HT) and tail-tail/tail-head (TT/TH) dyads in both the cis and trans regions of a One way to investigate the role of the catalyst in HT selectivity is via the polymerization of norbornene monomers substituted at the C5 or C6 position.

An HT bias in the polymerization of C5- and C6-substituted norbornene monomers with a given catalyst, particularly one that increases with decreasing polymerization rate (or increasing dilution), may point toward the existence of two or more distinct propagating species with characteristic HT bias.

Both results are likely a consequence of the increased steric hindrance caused by the endo substitution in monomer 3.18. Because initiators 3.1, 3.4, and 3.8–3.13 are stereogenic-at-Ru, the absolute configuration of the metal center is reversed at each. Enantiomeric (3.1) and diastereomeric (3.4) alkylidenes generated by the stereochemical inversion of the Ru metal center that occurs at each forward metathesis step.

Previous computational and experimental work has shown that cis-selectivity in cross-metathesis reactions mediated by cyclometallic catalysts similar to 3.1 and 3.4 arises from the steric influence of the bulky N-aryl group placed directly above the side-bonded metallacycle, resulting in the destabilization of the transition state leading to the formation of trans-olefins (described in more detail in Chapter 1 of this thesis).24 It is likely that the monomer approach in ROMP is similarly affected by the presence of the N-aryl group, in that norbornene and related monomers would be expected to respond to the less hindered exo plane, with the methylene bridge facing away from the N-aryl.

Table 3.10. Polymerization of Monomers 3.17 and 3.18 with Catalysts 3.1, 3.4, and 3.9

80 anti monomer approach to alternate sides of an anti alkylidene as a result of stereogenic

Isomerization of the alkylidene trans to NHC leads to the highly unstable intermediate 3.24. With the alkylidene trans to the NHC ligand, all complexes and 3.28 are very unstable and this process is generally very unfavorable. Then we investigated the possibility of isomerization via rotation around the alkylidene Ru=C double bond.

The alkylidene rotational barrier is only slightly affected by the steric bulk of the substituent on the alkylidene and the cyclometalated group on the catalyst.

Figure 3.10. Nonmetathesis-based polytopal rearrangement of ruthenium alkylidene 3.19 to its diastereomer 3.20

83 Table 3.11. Computed Alkylidene Rotational Barriers

Formation of a trans,syndiotactic or cis,isotactic dyad resulting from an anti or syn monomer approach, respectively, to a syn alkylidene following alkylidene rotation

The most favorable [2 + 2] cycloaddition transition state is the one leading to the formation of a cis,syndiotactic dyad, 3.31-TS-A, where the anti alkylidene reacts with a monomer approaching in an anti fashion. Ligand-substrate steric repulsions in this anti/anti approach are minimized due to the bulk of the monomer and alkylidene both. The second lowest energy transition state leads to the formation of a trans,syndiotactic arrangement (3.31-TS-C) in which the syn alkylidene reacts with an approaching monomer in an anti fashion.

Similarly, the transition states leading to the formation of trans, isotactic and cis, isotactic dyads (3,33-TS-B/D and 3,34-TS-B/D, respectively), although still very unfavorable, are also less destabilized with respect to to cis, syndioselective 3.33-TS-A and 3.34-TS-A.

Figure 3.11. [2 + 2] cycloaddition transition states for the polymerization of monomer 3.6 with catalyst 3.30

92 References

For a discussion of initiation in ruthenium metathesis catalysts, see: (a) Sanford, M

For computational studies on ROMP with non-cyclometalated ruthenium catalysts

All solvents were purified by passing through solvent purification columns and further degassed by argon bubbling. Single-point calculations were performed with M06 and a mixed basis set of SDD for ruthenium and 6-311+G(d,p) for. The single-point energy calculations used the SMD solvation model with THF as solvent.

This is the same level of theory used in previous calculations by the Houk group on ruthenium metathesis catalysts.

The residue was then dissolved in CH 2 Cl 2 and filtered over a pad of silica gel (eluent 10% MeOH in CH 2 Cl 2 ).

The solid was then filtered, washed with Et 2 O, dried, suspended in CH(OEt) 3 (25 mL) and refluxed for 2 h. After cooling the solution to room temperature, the solvent was removed in vacuo and the resulting solid residue was washed thoroughly with Et 2 O to give 3.41 (1.5 g, 37%) as an off-white solid. The resulting precipitate was filtered, washed with warm hexanes and further purified by column chromatography (SiO2, eluent pentane to 20% Et2O in pentane to DCM) to give g, 92%) as a green solid.

The solution was then washed with saturated NH4Cl (aq) (x2), dried over Na2SO4 and concentrated. The solution was then diluted with EtOAc, washed with saturated NH4Cl (aq) and brine, dried over Na2SO4 and concentrated. The solid was then filtered, washed with Et 2 O, dried, suspended in CH(OEt) 3 (10 mL) and refluxed for 2 h, at which point the solution was cooled to room temperature.

The resulting precipitate was filtered, washed thoroughly with hot hexanes and further purified by flash chromatography (SiO 2 , eluent pentane to 20% Et 2 O in pentane to CH 2 Cl 2 ) to provide g, 86%) as a green solid.

General Procedure for the Determination of Initiation Rates: In a glovebox, a 4 mL

General Polymerization Procedure: In a glovebox, an 8 mL vial with a septum cap was charged with catalyst (9.8 µmol) and THF (.84 mL) to make a stock solution (0.012 M)

The probability of forming a cis double bond in a species in which the last double bond formed is cis (Pc) is equal to the number of cc dyads present in the polymer divided by the total number of cx dyads (x = c or t ), or (cc)/(cc + ct). Calculations that also take into account the identity of the penultimate double bond require triad-level NMR analysis (see ref. 18 for peak assignments). For example, the probability of forming a trans double bond in a species in which the last double bond formed is trans and the penultimate double bond is cis (Ptc) is equal to the proportion of ctt triangles divided by all possible ctx triangles, or ( ctt)/(ctt + ctc).

Similarly, the probability of cis double bond formation in Ptt is 1/(1+rtt), where rtt = (ttt)/(ttc).

Figure 3.14. 13 C NMR (126 MHz, CDCl 3 ) spectrum of poly(3.5)/3.1.

124 Preparation of Poly(3.7) Using Catalysts 3.1–3.3: Poly(3.7) was prepared according to

130 Preparation of Poly(3.16) Using Catalysts 3.1 and 3.4: Poly(3.16) was prepared

134 Preparation of Poly(3.18) Using Catalysts 3.1 and 3.4: Poly(3.18) was prepared

Free energies and enthalpies (in brackets) for interconversion between ruthenium alkylidenes anti- and syn-(R,R)-3.32 via alkylidene rotation. All energies refer to the ruthenium alkylidene complex anti-(R,R)-3.4 and are given in kcal/mol. Free energies and enthalpies (in brackets) for interconversion between ruthenium alkylidenes anti- and syn-(R,S)-3.32 via alkylidene rotation.