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Metathesis Mechanism of Zinc-Catalyzed Fluorination of Alkenes with Hypervalent Fluoroiodine Jiji Zhang, Kalman J. Szabo, and Fahmi Himo ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02731 • Publication Date (Web): 19 Dec 2016 Downloaded from http://pubs.acs.org on December 19, 2016

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ACS Catalysis

Metathesis Mechanism of Zinc-Catalyzed Fluorination of Alkenes with Hypervalent Fluoroiodine

Jiji Zhang, Kálmán J. Szabó*, Fahmi Himo*

Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm (Sweden)

Corresponding authors: [email protected] , [email protected]

Abstract Density functional theory calculations are used to unravel the mechanism of the Zncatalyzed fluorocyclization reaction of alkenes using fluoro-benziodoxole reagent. In the initial step Zn coordinates to the fluorine atom of the fluoro-benziodoxole reagent. An important activation step for the fluorination involves Zn-mediated isomerization of the benziodoxole reagent. The activation is followed by a metathesis step to form the C-F bond, and a nucleophilic substitution, closing the ring to yield the final aminofluorination product. This mechanism has feasible energy barriers and accounts for the observed selectivity outcome. The alternative mechanism involving iodocyclopropylium cation intermediate is shown to be associated with high energies.

Keywords: fluorination, hypervalent iodine, mechanism, catalysis, metathesis, density functional theory

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Introduction Organofluorine compounds are very important species in pharmaceutical and agrochemical industries,1-3 and 18F labeled compounds are used in PET diagnostics.4,5 In the past decade a new era of fluorine chemistry started, characterized by the appearance of new safe and stable reagents and also the application of catalysis.6-9 Fluorination reagents based on hypervalent iodines have emerged as efficient tools to introduce carbon-fluorine bonds to organic substrates.7,10-13 Some of these reagents, in particular the R-IF2 (R = alkyl, aryl) type of species are very reactive fluorination agents.10,12,14,15 However, the high reactivity and the poor bench stability of these species somewhat limit their application in selective organic synthesis. A stable, easy to handle version of fluoro-iodine reagents is fluoro-benziodoxole 1,12,16 which very quickly found many applications.13,14,17-24 The reason is the facile synthesis,17,25 stability and high selectivity in the synthetic applications. Reagent 1 has a very low reactivity itself and in most applications catalysis was used for activation towards fluorination reactions.12 Very recently, Szabó and co-workers published a number of synthetic applications for fluorination of alkenes with 1.20-22 These metal-mediated reactions have similar initial steps and proceed with high selectivity and broad synthetic scope. One of the reactions involves fluorocyclization reactions, such as amino-, oxy and carbofluorinations.22 The activation mechanism of fluoro-benziodoxoles is in general poorly understood, which makes the development of new catalytic applications relatively difficult. In particular, understanding of the role of the steric and electronic factors in determining the selectivity would be very important to develop new regio- and stereoselective fluorination reactions using fluoro-benziodoxoles. Many aspects of hypervalent iodine chemistry have been elucidated using various computational techniques.26-33 In particular, mechanistic and modelling studies on the trifluoromethyl analog (Togni-reagent) of 1 have strongly contributed to the development of the field of catalytic trifluoromethylation reactions.34-41 Considering the importance and versatility of reagent 1 in organofluorine chemistry, we decided to explore the mechanism of the reactions using density functional theory (DFT) calculations. As a representative reaction, we selected zinc-catalyzed fluorocyclization of 2 with fluoro-benziodoxole 1 to obtain N-heterocyclic (piperidine) products (Scheme 1).22


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Scheme 1. Zn-catalyzed fluorination reaction investigated in the current study.

The catalytic cycle for the cyclization of 2 with 1 proposed by Szabó and co-workers in the experimental study is shown in Scheme 2.22 Following Togni’s mechanistic studies on activation of the analog trifluoromethyl-benziodoxole reagent,34 formation of complex A was suggested as the initial step of the aminofluorination reaction, where the zinc catalyst is coordinated to the oxygen atom of the benziodoxole structure.22 Subsequently, iodocyclopropylium cation B (Scheme 2) could form by cleavage of the I-O bond and coordination of the generated iodonium ion to the double bond of 2. Nucleophilic attack of the nitrogen on one of the corners of the iodocyclopropylium ring leads to intermediate C, which then undergoes cleavage of the carbon-iodine bond to give the final product 3 and regenerate the zinc catalyst. Similar initial steps have been suggested for the geminal difluorination of styrenes,20 opening of cyclopropanes,14 and iodo-fluorination of alkenes.21 To evaluate the energetic feasibility of this mechanism, and to examine the validity of the commonly proposed intermediacy of iodocyclopropylium B we conducted a DFT investigation using compound 2a (Scheme 1) as the model substrate in the study.


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F I

I

O

F

OH

Zn(BF4)2

+ N 3 Ts

1

OZnBF4

BF4 BF4

F I

OZnBF4

I F C

A TsHN

BF4 OZnBF4 NHTs I

F

2

TsHN B

Scheme 2. Previously-proposed mechanism for the aminofluorination of alkenes. 22

Computational Details All calculations were carried out using the B3LYP functional42 implemented in the Gaussian

09

program

package.43

For

geometry

optimizations,

the

LANL2DZ

pseudopotential with the corresponding basis set augmented with d polarization and p diffuse functions was used for I, LANL2DZ pseudopotential was used for Zn, and 631G(d,p) basis set was used for all the other atoms. The stationary points were confirmed as minima (no imaginary frequencies) or transition states (only one imaginary frequency) by analytical frequency calculations at the same theory level as the geometry optimizations. Based on these optimized geometries, single point calculations were carried out with the same basis set for I/Zn and the 6-311+G(2d,2p) basis set for all other elements. The reported energies are Gibbs free energies, which include solvation free energies. The latter are calculated as single-point corrections on the optimized structures using the SMD method44 with the parameters for DCM. The calculated energies were also corrected for dispersion effects using the B3LYP-D3 method of Grimme, with Becke and Johnson (BJ) damping.45


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Results and Discussion We first performed a computational speciation study in order to identify the lowestenergy complex that can be formed from the starting materials, which are the zinc salt Zn(BF4)2•xH2O, the fluoroiodine reagent 1, and the substrate 2a. Somewhat surprisingly, we found that the most stable Zn complex is a dicationic octahedral complex Zn(1F)62+ (termed React, Figure 1), in which all six ligands are fluoroiodine reagent 1 coordinated by its fluoro center (called 1F). In React, the I-F bond of the fluoroiodine reagent is elongated (from 2.01 Å to 2.17-2.24 Å) and the I-O bond is shortened (from 2.07 Å to 2.00-2.01Å) as compared to the uncoordinated reagent. All other considered complexes resulted in higher energies (see Supporting Information). Here, it should be stressed that the accuracy of the calculations of this speciation study is not expected to be very high because the energies involve ligand exchanges and changes of charge that could be problematic to treat accurately, especially considering the approximations made in the calculation of the entropy and solvation effects. Very importantly, however, the mechanistic conclusions are independent of the assumed starting complex, as will be discussed below.

Next, we considered the energetic feasibility of the proposed mechanism shown in Scheme 2, involving the iodocyclopropylium intermediate B. Change of the coordination mode to the zinc of one fluoroiodine from fluoro (1F) to oxo (called 1O) yields a complex Zn(1F)5(1O)2+ with slightly higher energy, +2.2 kcal/mol compared to React. Although the coordination of the oxygen to the Zn ion results in the elongation of the I-O bond (from 2.07 Å of uncoordinated 1 to 2.16 Å), it does not lead to its cleavage as previously suggested (Scheme 2). Very importantly, the putative iodocyclopropylium intermediate B could not be located. Approaching the alkene double bond of 2a to the iodine of 1O in Zn(1F)5(1O)2+ by a series of constrained geometry optimizations results in high energies (see Supporting Information). For example, at a distance of 2.2 Å the energy increases by as much as 28 kcal/mol. From these results it can be concluded that the mechanism proposed in Scheme 2 is not energetically viable.


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2.13 2.77

2.21

2.51

1.95

1.99 2.54

I-F = 2.17 – 2.24 I-O = 2.00 – 2.01 Zn-F = 2.02 – 2.10

2.00

1.95

2.62

Int1

TS1

React

2.35

2.18 2.76 2.32

2.00

2.16

2.87

2.71 2.56 1.99

1.45

2.23

1.50 1.53

1.43

TS2

TS2′′

Int2

3.07 2.49

3.28 2.75

2.21

4.06

2.24

3.27

1.50 1.96

Int3

TS3

Int4

Figure 1. Optimized structures of stationary points along the reaction pathway of Scheme 3. Selected bond distances are indicated in Å. Note that the zinc ligands in most structures are omitted for clarity.

Searching for alternative mechanisms that can rationalize the experimental findings, we obtained the pathway displayed in Scheme 3 that has very feasible energy barriers (Figure 2). The reaction starts with the isomerization of fluoroiodine such that the fluorine becomes trans to the phenyl carbon instead of the oxygen. The transition state for this isomerization step (TS1) is calculated to be 12.7 kcal/mol relative to React, and the resulting intermediate


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(Int1) is +10.1 kcal/mol. At Int1, the F-I bond distance is elongated to 2.62 Å due to the stronger trans-influence of the phenyl group,46 and the Zn-F distance is shortened to 1.95 Å. We note very interestingly also that at Int1 a fluoro atom from another fluoroiodine ligand forms a new interaction with the iodine center (F-I distance 2.51 Å), making it tetracoordinated square planar species (see Figure 1). This intermolecular interaction places thus two electronegative atoms at the axial positions of the iodine, similarly to what has been observed in the structure of the trimer of amino-acid derived benziodazol.47 This finding suggests that a fluoro-benziodoxole molecule coordinated to Zn assists the isomerization of another molecule (intermolecular F-I distance 2.77 Å at TS1, see Figure 1), lowering the activation barrier of the Zn-mediated process. Here, it is interesting to compare the obtained energies for the isomerization step with the uncatalyzed isomerization, i.e. without involvement of the zinc ion. The barrier to form the zinc-free Int1 analog is calculated to 31.0 kcal/mol and the reaction is endergonic by 16.7 kcal/mol (full energy profile is given in the Supporting Information). Clearly, coordination to Zn facilitates this step considerably. Very interestingly, a similar catalytic effect of Lewis acid was observed for the activation of phenyliodine diacetate (PIDA). It has namely been demonstrated that coordination of BF3 promotes the isomerization of PIDA, which facilitates the further reaction of the species.48,49 In the next step of the reaction mechanism, substrate 2a enters and engages in a metathesis reaction with the isomerized hypervalent iodine (Scheme 3). At the transition state (TS2, Figure 2), two σ-bonds are forming (I-C1 at 2.32 Å and F-C2 at 2.00 Å), the I-F bond is breaking (2.76 Å), and the C1=C2 double bond is becoming a single bond (1.45 Å). TS2 is calculated to be 9.1 kcal/mol higher than Int1, i.e. 19.2 kcal/mol relative to React. The resulting intermediate Int2, in which the fluorine is coordinated to the zinc, is calculated to be 3.0 kcal/mol lower than the transition state, i.e. +16.2 kcal/mol relative to React. However, a lower-energy intermediate could be located in which the oxygen is coordinated to the zinc (Int3). Int3 is calculated to be 18.4 kcal/mol lower than Int2, i.e. -2.2 kcal/mol relative to React. Transition state for metathesis reaction occurring directly at React, i.e. without the isomerization step, could also be located, but the barrier was calculated to be very high, 39.5 kcal/mol (see SI for optimized structure). Also for the metathesis step, the involvement of the zinc ion is crucial in order to lower the barrier, since without zinc the barrier is calculated to be 34.5 kcal/mol (see SI).


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Scheme 3. Mechanism of the zinc-catalyzed aminofluorination reaction proposed on the basis of the current calculations.

In Int3 the amino group can now make a nucleophilic attack at the terminal carbon C1, forming the ring and releasing the iodine. The optimized transition state for this step (TS3) is shown in Figure 1. The calculated barrier relative to Int3 is 23.1 kcal/mol, which is the rate-determining barrier of the process. This step is quite exergonic, as the generated intermediate Int4 is 10.4 kcal/mol lower than Int3 (-12.6 kcal/mol relative to React). To close the catalytic cycle, a proton moves from the nitrogen to the oxygen to produce the final aminofluorination product, and a ligand exchange takes place to regenerate the starting Zn(1F)62+ React complex. The proton transfer takes place spontaneously from the positively-charged nitrogen to the negatively-charged oxygen during the geometry optimization once the NH group is rotated to form a hydrogen bond to the oxygen. This shows that the step is either barrierless or associated with a very low barrier. Combined, the proton transfer and the ligand exchange steps are calculated to be exergonic by 32.5 kcal/mol, which makes the overall cycle exothermic by 45.1 kcal/mol (Figure 2).


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[Zn]

O [Zn]

F

I

O

F

I

2a

TS1

I

NHSO2Ph

NHSO2Ph

O [Zn]

F

TS3 20.9

TS2 19.2 16.2

12.7

Int2 10.1 Int1

[Zn] [Zn]

O F

O [Zn]

0.0 [Zn]

F

I

O

F

O I

F

I -2.2

NHSO2Ph

I Int3

NHSO2Ph

Int4 [Zn] O F

-12.6 F

1

I

HO

React

I

[Zn] = Zn(1F)52+

+

NSO2Ph

NHSO2Ph -45.1 [Zn]

F

I

O

Figure 2. Calculated free energy profile for the zinc-catalyzed aminofluorination.

The obtained mechanism of Scheme 2 has thus very feasible reaction barriers that are consistent with the reaction time and temperature of the experiments (Scheme 1). 22 Very importantly, the proposed mechanism is also consistent with the regioselectivity of fluorination reaction. The metathesis transition state TS2 gives the product observed experimentally, i.e. fluorination at the C2 carbon. The reverse transition state (TS2′′, Figure 1), in which the C1-F and C2-I bonds form, instead of C1-I and C2-F bonds, is calculated to be as much as 16.4 kcal/mol higher than TS2. Clearly, the negative charge at the fluorine atom in Int1 (NBO charge -0.77) prefers the more substituted C2 carbon (charge -0.01), while the iodine (charge +1.38) prefers the less substituted terminal C1 carbon (charge 0.45). As discussed above, the computational speciation study indicates that Zn(1F)62+ (React) is the lowest-energy complex. However, as these energies could be associated with large inaccuracy, we have examined the feasibility of the obtained reaction mechanism of Scheme 3 starting from eight other structures of the zinc catalyst, with different coordination numbers and total charges. The calculated energy graphs are shown in Figure 3 and give a consistent picture with the mechanism of Scheme 3. The same reaction sequence is obtained, with overall rate-limiting barriers in the range of 15-26 kcal/mol, depending on the starting complex. In addition, in all the cases, the experimental regioselectivity is reproduced, as the metathesis transition state TS2 is always found to be much lower in energy compared to the alternative TS2′′ (see Supporting Information).


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19.2 12.7

Zn(1F)62+

20.9 16.2

10.1 18.3

0.0 10.7

Zn(1F)52+

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13.5

-2.2

14.5

8.3

0.0

-12.6 17.3

13.4

14.9

-5.7

9.4

-21.1

5.2 Zn(1F)42+

0.0

23.0

14.6 8.8

Zn(BF4)(1F)5+

11.1 6.9

1.9

0.0

14.6

11.3

10.1 4.7

Zn(BF4)(1F)4+

-6.4

0.0

16.6

13.9

-25.2

7.2 0.7 14.5

14.4

-13.3

10.2 Zn(BF4)(1F)3+

0.0

21.5

19.3

3.5 17.6

25.6

-20.4

11.2 4.1 Zn(BF4)2(1F)4

Zn(BF4)2(1F)3

0.0

17.8 13.1

10.3

13.3 20.1

0.0

-21.6

11.0 20.3

-8.3

2.3 14.3

11.9 8.1 Zn(BF4)2(1F)2

3.3

0.0

-20.1

-21.1

Figure 3. Calculated free energy profiles for zinc-catalyzed aminofluorination starting from different zinc complexes. The one starting from Zn(1F)62+ (React, Figure 2) is given again for comparison.

Considering the important role of the zinc ion as a Lewis acid, we investigated whether hydrogen bonding to the NH group of the substrate could play a similar role in a selfcatalyzed reaction. However, the calculated free energy profile (Figure 4) shows that the barrier for the metathesis step is not lowered much compared to the uncatalyzed reaction, from 34.5 to 32.2 kcal/mol. Very interestingly, Yan et al have very recently reported a DFT study50 on the mechanism of fluorocyclization of o-styryl benzamide with fluoro-iodoxole 1,16 highlighting the difference in chemoselectivity between this reagent and Selectfluor. It was shown that hydrogen bonding to the benzamide group of the substrate activates the fluoroiodane reagent


10

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ACS Catalysis

and catalyzes the C-F bond formation, following essentially the mechanism discussed above involving isomerization and metathesis, although these steps were not recognized as such.50

O

R N H

R

F

N H

O N R S SO2Ph O Ph

NHSO2Ph

O S O Ph

32.2 28.7

2a 2a

O H

20.1

17.8

13.4

O

0.0 F

I

R N H

PhO2S

N H

O F

H O N S O R Ph

1 R=

Ph S O O

F

I F

O

R N

I

2a

I

R N Ph S O O H

I

H N

23.8

F

I

F

I

PhO2S

O F

O H

I

O H

NHSO2Ph N H PhO2S

R N Ph S O O

SO2Ph

O S O

H N R Ph

-3.1

H O N O S R Ph

Figure 4. Energy profile for substrate-assisted aminofluorination.

In this context, it also very interesting to compare the energies obtained above for the Zncatalyzed reaction to the case of the fluorolactonization reaction reported by Stuart and coworkers and that occurs without any external catalyst.19 In this case, the carboxylic moiety of substrate 4 acts as a Brønsted acid, catalyzing the reaction. We have studied this case as well and located all transition states and intermediates. The calculated energy profile is given in Figure 5. The barriers for the fluoroiodine isomerization (TS1-acid), metathesis (TS2-acid) and nucleophilic substitution (TS3-acid) steps are calculated to be 19.0, 28.6, 27.5 kcal/mol, respectively. From these energies it is thus clear that the carboxylic acid moiety is sufficient to catalyze reaction following the same reaction sequence as in Scheme 3.


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F

O

I

1 (1.5 equiv)

OH

Ph

4

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O

Ph F

O

4Å MS, CH2Cl2, 40 °C, 18h

O

H

R'

O

O H O

R'

O

O

H O

O

I

O O O H O

F

O

H

F

I

F

Ph

I

TS2-acid O

TS3-acid

28.6

27.5

R' TS1-acid 19.0

17.2

2x4

Int2-acid

H O

15.5

4 6.1

O O

Int1-acid

0.0

H F

I

R'

O F

I

Ph

O

O F H

O

Int3-acid H

O O H

I

R'

O H

I

H O

O O

O

O

R'

O

Ph

H O

O

O

O

R'

O

R'

I

F Int4-acid -29.3

Ph F Ph

R' =

Figure 5. Metal-free fluorolactonization reaction by Stuart and co-workers19 (top), and calculated free energy profile for the reaction (bottom).

These calculations show thus that both a Lewis and Brønsted acids can activate fluororeagent 1 and catalyze the C-F bond formation. The activation mechanism of 1 described above is a very interesting feature. As mentioned above, this reagent is benchstable and unreactive in the absence of the catalyst. The calculations show that the energy of the LUMO of isolated 1 is decreased considerably due to the isomerization, from -1.1 to -2.3 eV. This indicates that electron acceptor ability of fluoro-benziodoxole is increased by isomerization, making the isomerized reagent a much better (and more reactive) electrophile than 1 in the ground state structure. Furthermore, coordination of the isomerized reagent to the Lewis or Brønsted acid leads to electron withdrawal that results in further increase in electrophilicity. Similar conclusions were reported recently for the activation of PIDA, where it was found that the LUMO energy decreased by the isomerization and coordination of Lewis acid.48


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Conclusions In summary, we have in the present paper employed DFT techniques to investigate the mechanism of the Zn-catalyzed fluorocyclization reaction of alkenes using fluorobenziodoxole reagent. The

involvement

of

the

originally

proposed

mechanism

(Scheme

2)

via

iodocyclopropylium cation intermediate is first calculated to have prohibitively high energies. Instead, an energetically feasible mechanism is proposed, in which the fluorobenziodoxole reagent first coordinates to the zinc ion by its fluorine center (Scheme 3). According to this mechanism the reagent is activated by an isomerization step such that the fluorine center becomes trans to the phenyl carbon of the reagent. A metathesis step takes then place, forming the C-F and breaking the F-I bond. Finally, a nucleophilic substitution closes the ring to yield the product. Very importantly, this mechanistic proposal rationalizes the experimentally observed regioselectivity. The zinc ion is demonstrated to lower the barriers of all steps of the reaction, and calculations assuming nine different zinc complexes give a very consistent picture of the mechanism. Moreover, the same reaction mechanism is shown to be operative also in the case of the fluorolactonization reaction, in which the carboxylic moiety of substrate acts as a Brønsted acid facilitating all three steps of the reactions. We believe therefore that the mechanism proposed here for fluorocyclization can be generalized to other Lewis and Brønsted acid-catalyzed fluorination reactions using the fluoro-benziodoxole reagent.51

Supporting Information Supporting Information Available: Computational speciation study. Optimized structures of Zn(1F)5(1O)2+ and TS1′′. Constrained geometry optimizations for the formation of the iodocyclopropylium intermediate. Energies of TS2′′ starting from different zinc complexes. Complete energy profile for the uncatalyzed reaction. Absolute energies and energy corrections. Cartesian coordinates of optimized structures. This material is available free of charge via the Internet at http://pubs.acs.org.


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Acknowledgements Financial support from the Swedish Research Council and the Knut and Alice Wallenberg Foundation is acknowledged.

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Table of Contents Graphics

O

Zn F

R2 R 3 NHTs

R1

R2

+ F

I

O

I

R1 NHTs

R3 Metathesis TS

R2

F R1

R3 N Ts


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Metathesis Mechanism of Zinc-Catalyzed ... - ACS Publications

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