Baran Group Meeting
4/12/14
Hydrogen Atom Transfer
Julian Lo
1. Introduction
2. Polarity Reversal Catalysis
Hydrogen atom transfer (HAT) is a concerted movement of a proton and an electron (i.e., H•)
in a single kinetic step from one group to another. (Mayer, J. Am. Chem. Soc. 2007, 5153)
A useful concept in HAT is radical polarity. Despite being uncharged species, radicals can
have nucleophilic or electrophilic tendancies.
A—H +
B•
A•
+ B—H
By definition, HAT is intimately linked to organic free readical chemistry, with one of the
most useful hydrogen atom transfers in organic synthesis being the termination of a carbon
centered radical with Bu 3SnH. (Curran, Tetrahedron Lett. 1985, 4991)
Me
Me
Br
nBu 3SnH
AIBN
PhH, 80 °C
Me
Me H
Me Me
HH
H
Some practice:
nBu 3SnH
Me Me
HH
tBuO
Me
nucleophilic
radicals
H
tBu
more stable
Although nBu 3SnH is a great hydrogen atom
donor (BDE = 78 kcal/mol), it's toxicity is a
well-known problem and it can be difficult to
purify nBu 3SnX byproducts away from the
desired product.
- e–
nucleophilic
radical
HAT
H
Me
9(12)
∆
-capnellene
A
+ e–
electrophilic
radicals
A
A qualitative approach to determining the "philicity" of a radical
1. Consider the oxidized (cationic) and reduced (anionic) forms of A•
2. Determine which of the forms is more stable
3. Assign the "philicity" of the radical:
a. If A+ is more stable, A• is a nucleophilic radical because it wants to lose an e –
b. If A– is more stable, A• is an electrophilic radical because it wants to gain an e –
Me Me
H
Me
Me
Me H
- e–
A
Et 3Si
more stable
- e–
nucleophilic
radical
- e–
nucleophilic
radical
tBuO
+ e–
tBuO
electrophilic more stable
radical
Quantitative treatments of
radical "philicities" have also
been developed. (Fisher,
+ e–
Angew. Chem. Int. Ed.
tBu
tBu
electrophilic
2001, 1340; Héberger, J.
radical
Org. Chem. 1998 , 8646; De
Proft,
Org. Lett. 2007, 2721)
+ e–
Et 3Si
Et 3Si
electrophilic
radical
Just like Sn2 reactions, polarities of the reactants should be matched for favorable reactivity.
Procedures that are catalytic in tin have been
developed. (Fu, J. Org. Chem. 1996, 6751)
O
Me
Me
nBu 3SnH
(10 mol%)
PhSiH 3 (1.2 eq.) Me
Me AIBN, PhMe, ∆
Me
O
El •
+ Nuc–H
Nuc• +
El–H
El–H
El1• + El 2 –H
Me
(80%)
Several reviews have been published on
alternatives to Bu 3SnH and other stannane
reducing agents; several of these topics will
not be discussed. (Walton, Angew. Chem. Int.
Ed. 1998, 3072; Studer, Synthesis 2002, 835;
Chatgilialagou, Chem. Eur. J. 2008, 2310)
Nuc1• + Nuc 2 –H
+ Nuc•
Nuc–H +
El •
El1 –H +
El 2•
Nuc1 –H + Nuc 2•
favored
disfavored
These classifactions
represent polar effects
in the transition states
E.g., trialkyl silanes are typically awful at homolytic reduction of functional groups via HAT.
Et 3Si• +
R–X
R • + Et 3Si–H
Nuc1•
Nuc 2–H
fast
unfavorable
polarity
mismatch
R•
Et 3Si–X
+
R–H
Nuc1 –H
+ Et 3Si•
Nuc 2•
Replace with two steps
that are polarity matched?
Adding a catalyst that replaces the polarity mismatched step with two polarity matched ones
should yield a net favorable reaction. This known as polarity reversal catalysis (PRC).
R• +
Nuc•
R'S–H
El–H
R–H
Nuc–H
favorable
R'S • + Et 3Si–H
El•
Nuc–H
R'S–H
El–H
favorable
R'S •
El•
+
+ Et 3Si•
Nuc•
Me
Br
Me
tC12H 25SH
(1 mol%)
C6H12, ∆
H
O
Me
O
H
O
O
O
Ph 3SiH
TBHN
O
MeS
O
Me
O
H
Me 1,4-dioxane
60 °C
Me
S
In situ formation of polarity reversal catalyst:
O
-MeSSiPh3
Ph 3Si•
O C S
MeS
SSiPh 3
90%
O
H
O
-CO
polarity
Ph 3SiS H
reversal cat.
Ph 3SiH
Ph 3SiS•
H 2O
Me CO2R
O
Me Me
O
O
1
30
Me
25
1
Me 3N BH 2Thx
H
H H
2
(tBuO) 2
140 °C
R
26–57%
tBuO
Me CO2R
CN
CN
-CO2
-PhMe
O
competitive processes:
Me CO2R
CO2R
-Me
2
R
catalyzed
CN
+
tBuO•
Me
Me Me
Nuc•
CN
MeSH or Ph 3SiSH
polarity reversal cat.
uncatalyzed
O
(anti)aromaticity
of the
oxidized and reduced forms
of the radicals can be used
to rationalize the outcome
+
Me 3N BH 2Thx
"Pro-aromaticity" can be used to drive radical chain reactions.
(Walton, J. Chem. Soc., Chem. Commun. 1995, 27)
SSiPh 3
H
H
Me 3N B
Me HAT
Me
(tBuO) 2, hυ
3. Reagents Derived from 1,4-Cyclohexadiene
O
H
O
Catalyst-controlled enantioselective HAT utilizing a polarity reversal catalyst.
(Roberts, J. Chem. Soc., Perkin Trans. 1 1998, 2881)
R
Ph 3SiH
R
R
OAc
TBHN
R
OAc
H
AcO
O
1 (5 mol%)
O
O
AcO
SH
O
O
60 °C
SiPh 3
1
84%, 76% ee
R = Me
90%, 95% ee
R = Ph
Amine-alkylboranes can be used to alter regioselectivity of HAT via PRC.
(Roberts, J. Chem. Soc., Perkin Trans. 2 1989, 1953)
Me 3N B
H
O
86%
Me
Me
MeS
Me
Me 3N BH 2Thx
H
no cat.
cat.
O
Ph 3SiS
H
+
O
O
(tBuO) 2, hυ
H
H no catalyst gives
O
complex mixture
only radical observed
An example that can best be rationalized by radical "philicities."
(Roberts, J. Chem. Res. (S) 1988, 264)
Me
Me
O
Me R
H
H
99% vs 10%
Br
H
without RSH
However, using R 3SiH in Barton-McCombie reactions proceeds very efficiently.
(Roberts, Tetrahedron Lett. 2001, 763)
Me
Me R
Me
Favorable polar effects in
the transition states for the
two PRCed steps lowers
the E a of the overall
unfavorable transformation
Thus, adding a catalytic amount of thiol to Et 3SiH reductions of alkyl halides dramatically
improves the yield. (Roberts, J. Chem. Soc. Perkin Trans. 1 1991, 103)
Me R
Et 3SiH
Me H
DLP (2 mol%)
Me
Me
Baran Group Meeting
4/12/14
Hydrogen Atom Transfer
Julian Lo
R
up to 51%
R
2
R H
up to 37%
Replacing Me in 2 with Ph led to a cleaner reaction.
(Walton, J. Chem. Soc., Perkin Trans. 1 2002, 304)
O
Ph
O
O
tBuO2Bz
tAmylOH
100 °C
66%
no observed loss of Ph•
+ Ph Ph
O
low (~20%) yields of
intermolecular additions
The "pro-aromaticity" concept can also be applied to generate carbamoyl radicals.
(Walton, J. Org. Chem. 2004, 5926)
OTr
N
DLP
Me
cat. RSH
O
Bn
N
PhH, ∆
N
Me
Bn
Mech?
O
68%
The BDE of H 2O was proposed to decrease upon complexation with TiIII.
(Oltra, Angew. Chem. Int. Ed. 2006, 5522)
R2
Cp Cl
Cp Cl
Cp
H R2
H 2O
R1 R 3
Ti
Ti
+ Cp O
Ti Cl
Cp O H
Cp
R1 R 3
H
H
BDE calc = 49.4 kcal/mol
And the system was found to be applicable to reductive openings of other epoxides.
Me
AcO
Cp
2 Cp
Me
alkyl radicals
hydroxyformyl
radicals
CO2Me
radical
hydroamination
Bu 3SnH substitute
transfer hydrosilation
Me
Me
O
Cp2TiCl
THF
O
anhydrous
with H 2O (28 eq.)
with D 2O (28 eq.)
H
Me
3
4
97
15
25
3
85
75 (70% D)
[TiIV ]
O
AcO
H
Me Me
Cl
Ti
O H
H
H
H ML n
ML n
H
Me
H
Me O
4
Me
Me
O
nC10H 21
OH
85%
H
or
H
H
R
R
R or
R
H
R
O
Cp2TiCl2 (10 mol%)
Mn 0, Coll•HCl, H 2 (4 atm)
HO
RhCl(PPh 3)3
(5 mol%)
Me
Cl
9
Proposed mechanism:
OH
[TiIV ]
+ Collidine Coll•HCl O
H
R
R
[RhII ] H
H
R
[TiIV ] Cl
R
0
0.5 Mn
0.5 MnCl 2
H
Me O
H
Me Me
43%
R
R
R
Me
OH
Me
O
3
Me
Me
O
+
O
nC10H 21
Works with Pd/C,
Pd/Al 2O 3, Pd(dba) 2,
Wilkinson, Lindlar
A similar reductive epoxide opening has been developed that occurs via a catalytic bimetallic
system using H 2 as the terminal reductant (Gansäuer, J. Am. Chem. Soc. 2008, 6916)
4. HAT from Unlikely Sources
The identification of a trace byproduct led to an interesting discovery.
(Oltra, J. Org. Chem. 2002, 2566)
OH
O
Me
O
O
OH
Me
Double HAT from the same Ti complex to conventional [H] catalysts allowed for
alkene and alkyne reduction. (Oltra, Org. Lett. 2007, 2195)
Several other 1,4-cyclohexadiene derived reagents have been developed.
(Walton, Acc. Chem. Res. 2005, 794)
Me NHBoc
R CO2H
Ph CO2H
Me TBS
MeO
OMe
Me
Baran Group Meeting
4/12/14
Hydrogen Atom Transfer
Julian Lo
IV
[TiIII ] [Ti ]
O
R
R
R
[RhI ]
[TiIV ]
R
O
R
R
III
H [Rh ] H
O
R
R
O
Cl
9
H2
[TiIV ]
H
A similar system employing
IrCl(CO)(PPh 3 )2 allows for
cyclization
of
radical
intermediate onto alkenes
and alkynes. (Gansäuer, J.
Am. Chem. Soc. 2011, 416)
A curious observation was made en route to the phomoidrides.
(Wood, J. Am. Chem. Soc. 2005, 12513)
E
Et
O
O
O
E
desired
E
E
C 4H 9
R 3B
C 4H 9
C 4H 9
E
Et
O
E
C 4H 9
not
desired
Me H
B O
Me
H
Me
B O
Me
H
Me
Me
-Me
H
O
99% for Me 3B
Me
B O For entire process,
Me
H ∆H calc = 73 kcal/mol
The reaction was shown to be general.
Me
O
Me
H
O
O
SMe
SMe
O
O
O
Me Me
Me R
S
Me
91%
Me
77%
Me
SMe
S
S
H
SMe
H
O
S
C12H 25
H
O
71%
B OMe
O
OH
B R
R H
R
Me
Me
(cat)BH
MeOH
DMA
(10 mol %)
air, DCM, ∆
Me
Me
B O
OH
SH 2
Schwartz's reagent was found to serve as an efficient HAT donor in radical cyclizations.
(Oshima, J. Am. Chem. Soc. 2001, 3137)
H
O
O
O
O
competitive
Cp2ZrCl2/Red-Al
hydrozirconation
R
72–94%
X
was rarely
Et 3B, air, THF
H
H
observed!
R
R R
X = Br, I
O
Proposed mechanism:
O
O
R
X
H
Cp2ZrIV
Cl
Et
Et
R
R
+
Cp2ZrIV
Cl
O
H
Cl
O
R
O
H
R
X
R
O
1
Cp2ZrIV
Cp2ZrIII
Cl
+
9
O
X
H
Me
Me
Me
OH
4-tert-Butylcatecol was shown to be superior to catechol (J. Am. Chem. Soc. 2011, 5913)
O
Me
Me
O
O
R
It was found that B-alkylcathecholboranes could be reduced to alkanes via a
radical decomposition pathway. (Renaud, J. Am. Chem. Soc. 2005, 14204)
R
O
O
42%
Me
+ (MeO) 3B
OH
A similar system was used to reduce alkyl iodides (3º, 2º, 1º) to the corresponding alkanes
in good yields (65–97%). (Wood, Org. Lett. 2007, 4427)
B(cat)
OH
MeOH
O
OH
BDE calc = 86 kcal/mol
O
O
Therefore, the following mechanism was proposed:
O
Upon extensive deuterium labeling studies, authors found that adventitious H 2O was
the H• source, and proposed:
Me
H 2O
B
Me
Me
OMe
H
O O
Me
not observed!
B
O
O
The authors originally proposed an "ate" complex to be responsible for HAT, but it was not
observed by 11B NMR—only the methanolysis products were.
(Renaud, Chem. Commun. 2010, 803)
O
O
E
air,
PhH
S
Et
E
Et
SMe
Me
Baran Group Meeting
4/12/14
Hydrogen Atom Transfer
Julian Lo
H
R
Cp2ZrIV
H
Cl
H
O
H
R
R
5. Olefin Reduction by Transition Metal Hydrides
A general mechanism for HAT reduction of activated alkenes was supported by CIDNP effects.
(Halpen, J. Am. Chem. Soc. 1977, 8335)
Mn(CO) 5
Me
Me
Me
+ HMn(CO) 5
+ Mn(CO) 5
cage
Ph
Ph
Me
Ph
Me
escape
solvent caged
("geminate") radical pair
HMn(CO) 5
fast
Deuterium studies with DMn(CO) 5:
1. First HAT to alkene is reversible
2. Inverse deuterium effect observed Mn (CO)
2
10
consistant with the proposed RDS (C–H
bond being formed is stronger than the
M–H bond being broken)
fast
H Me
Mn(CO) 5 +
Ph
Against hydrometallation mech.:
HCo(CO) 4
N 2 or CO
DCM, 0 °C
Ph
H
Ph
krel(N2) = 1.0
krel(CO) = 1.1
solvent
krel
DCM
hexanes
acetone
MeCN
1.0
1.1
0.9
0.9
Ph
Me
DWCp(CO) 3 or
DMoCp(CO) 3
Ph
D
Ph
not observed!
krel
substrate
Ph
Me
1
Me
N
tBu
Ph
HMn(CO) 5 and HCo(CO) 4 can also undergo a HAT to allenes.
(Garst, J. Am. Chem. Soc. 1986, 1689)
H
H
Me
Me
Me
Me
Me
Me
ML n
Me
Me
Me Me
Me Me
Me
Me
~0.02
Me
nC5H11
24
CO2Me
The kinetic data was used to develop substrates that could participate in a HAT-mediated
cyclization. (Norton, J. Am. Chem. Soc. 2007, 770 and Tetrahedron 2008, 11822)
O
MeO 2C
D
Ph
observed!
R
Ph
HCrCp(CO) 3
(7 mol%)
Ph
2 atm H 2
50 °C
CO2Me
MeO 2C Me Ph
Me
Ph
R
MOMO
R
R = H, 4 days, 62%
R = CO2Me, 1.5 days 95%
R
Me CO2Me
(23%)
HCrCp(CO) 3 was also shown to reduce alkynes, but the substitution pattern on the
alkyne sometimes led to odd products. (Norton, J. Am. Chem. Soc. 2012, 15512)
Me
Me
Me
Ph
Me
MeO 2C
Me
≤5 x 10 -4
CO2Me
≤5 x 10 -3
HCrCp(CO) 3
Ph
Ph
+
PhH
9
Me
CO2Me
Me
Me
≤2 x 10 -4
tBu
N
O
27
Ph
Ph
Ph
DCrCp(CO) 3
134
Me
780
nC6H13
CO2Me
Ph
krel
substrate
Ph
But failed radical trapping:
Me
krel
substrate
Ph
But revealed that the reversibility of the 1st HAT was dependent on the TM–H.
(Sweany, J. Organomet. Chem. 1981, 57; Norton, J. Am. Chem. Soc. 2007, 234)
Me
Like most other reactions, the rate of HAT reduction by HCrCp(CO) 3 was substantially
affected by olefin substitution. (Norton, J. Am. Chem. Soc. 2007, 234)
Ph
Against polar mech.:
Ph H
Differences in deuterium labeling studies showed that HAT to the allene was irreversible.
D
Me
Me DCo(CO) 4
Me
D/H?
Me Me
Me
Me
Me
DCo(CO) 4
Me
D
Me Me
Me Me
Me
Later studies on different early TM–H generally supported analogous mechanisms and
provided additional evidence to disprove alternative pathways...
(Orchin, J. Organomet. Chem. 1979, 299)
Ph
Baran Group Meeting
4/12/14
Hydrogen Atom Transfer
Julian Lo
CO2Me
HCrCp(CO) 3
PhH
Ph
Me
1
CO2Me
CO2Me
Different mechanisms were proposed to account for the different outcomes:
HCrCp(CO) 3
+
R
R'
SET
E
E
R = CO2Me
R' = CO2Me
Additionally, a later report provided evidence for a radical-based pathway initiated by HAT.
(Isayama, J. Synth. Org. Chem. Jpn. 1992, 190)
HAT
Ph
R = Ph
R' = H
PhO 2SN
E
E
Ph
H
OC Cr
OC CO
Ph
high
[HCrCp(CO) 3]
Ph
HO
cage escape
low
[HCrCp(CO) 3]
H
Ph
Ph
Ph
Ph
6. Olefin Hydrofunctionalizations
A simple olefin hydration has spurred a plethora of research in the area of HAT-based olefin
hydrofunctionalizations. (Mukaiyama, Chem. Lett. 1989, 1071)
4
OH
Ph
PhSiH 3, O2
THF, rt
O
O
4
O
The intermediacy of a cobalt peroxide
adduct was suggested:
O
R
R
O
Me
O
+
Ph
O
R
SiPhH2
Me
4
O
84%
O
O
14%
OH
CoL2
Me
R
Me
CoLn
Me
O H
R
Me
O
-H•
R
PhO 2SN
Me
Me
Me
50%
Co(acac)2 + NaBH 4
L nCo–H
(Chung, J. Am. Chem. Soc. 1979, 1014)
cat. Mn(dpm) 2
R1
PhSiH 3, O2
CO2R
cat. Mn(dpm) 2
PhSiH 3, O2
R1 = Ph
R1 = Me
R2
2
R = Ph
R2 = H
Selectivity seems to follow Norton's observations!
OH
Me
CO2Bn
91%, exclusive
Mn(dpm) 3 also catalyzed the same reaction, but the products formed were dependent on the
presence or absence of oxygen. (Magnus, Tetrahedron Lett. 2000, 9725 and Tetrahedron
Lett. 2000, 9731)
HO Me
Co(acac)2
(5 mol%)
CO2Et
Ph Ph
73%, exclusive
Ph
Ph
OH
PhO 2SN
Electron difficient olefins were also hydrated, but some substrate dependent regioselectivity
was observed. (Mukaiyama, Chem. Lett. 1990, 1869)
The product distribution arising from the reduction of PhC≡CPh was dependent on time.
O
PhSiH 3, O2
DME, rt
Could a cobalt hydride
be responsible for HAT?
Ph
E
O2 or CoLnOO•
cat.
Co(acac)2
HAT
E
H
Ph
Baran Group Meeting
4/12/14
Hydrogen Atom Transfer
Julian Lo
Me
O cat. Mn(dpm) 3
PhSiH 3
with O 2
iPrOH
Me
Me
O cat. Mn(dpm) 3
PhSiH 3
O
without O 2
iPrOH
Me
Me
"We have also
observed that the
way in which the
reaction flask is
washed influences
the
product
distribution."
Authors proposed that oxygen activation of the Mn hydride is responsible for the divergent
outcomes:
R2
no
H
R 2 iPrOH
R2
O
R1
O2
O
O
Mn
(dpm) 2Mn
O
O
O
R1
O
R1
H
O
O
Mn
R2
O
O
H
HO
1
O
O
R 2 P(OEt) 3
R2
O2
O
R
O
O
Mn
O
O
(dpm) 2Mn
O
O
R1
O
R1
O
Baran Group Meeting
4/12/14
Hydrogen Atom Transfer
Julian Lo
Additionally, similar conditions have been shown to proceed through a HAT mechanism.
(Shenvi, J. Am. Chem. Soc. 2014, 1300)
Me CO2Et
H
Me
cat. Mn(dpm) 3
Me
PhSiH 3
CO2Et
CO2Et
CO2Et
Me
TBHP
iPrOH
Me
H
Me
10:1 dr
7. Transition Metal Oxo Compexes
When the rates of benzylic C–H oxidation by MnO 4- in nonaqueous solutions were examined,
they were found to show a Polanyi relationship. (Mayer, Inorg. Chem. 1997, 2069)
O
Me
rt
O +
O
+ nBu 4NMnO 4
MnO 2 +
1 week
(31%)
A hydrohydrazidonization and hydroazidonation using similar conditions have been reported.
(Carreira, J. Am. Chem. Soc. 2006, 11693)
Boc
N
N
Boc
cat. Mn(dpm) 3 or 5
PhSiH 3
0 °C or rt
Mn(dpm) 3:
5:
Some opening of vinyl
cyclopropanes was observed,
suggesting
that
radical
intermediates are involved.
The Polanyi relationship is
specific to HATs that states for a
given system, there is a linear
relationship between activation
parameters (log k) and BDEs
(∆H°)
of
the
substrates
L H
O
N
Co
Me
O
N
Me
O
Boc
N NHBoc
Me
Me
5
98%
66%
OO
So if a Polanyi relationship is
observed, the reaction is likely to
involve a HAT as the ratedeterming step
Boc
Ph N NHBoc
+ ring-opened
mixture
Me
Ph
5:
Mn(dpm) 3:
48%
60%
20–30%
20%
A HAT mechanism (molecule-assisted homolysis) was proposed to occur based on the
Polanyi relationship and other kinetic evidence. (Mayer, Science 1995, 1849)
H H
However, neither of the proposed mechanisms invoked HAT :
Boc
H
N
R
N
Boc
SiPhH2
N
Boc
EtOH Boc
N
R
Me
R
Ph
CoIII H
R
N
N
CoII
Me
CoIII H
Boc
Boc
Boc
N
N
R
Boc
Me
path A
CoIII
R
+ O MnO
3
Ph
path B
H
R
CoII
Me
Boc
H
H H
O MnO 3
Ph
+ HO MnO
3
... but two radical species generated?
For metal oxo species, HAT reactivity is determined by strength of bond being formed, not
electronic structure of oxidant.
PhSiH 3
CoIII
N
Boc
Boc
N
R
H
H H
no radical character...
Me
(trace)
N
N
Boc
The bond strength of the formed
H–OMnO 3- was calculated to be
80 kcal/mol [between that of
ROOH (89 kcal/mol) and HI (70
kcal/mol)]
Another
Polanyi
relationship
shows that MnO 4 abstracts H• at
approximately the same rate as a
theoretical O-centered radical that
also has a O–H BDE of 80
kcal/mol
Hydrogen Atom Transfer
Julian Lo
Other transition metal oxo complexes that react via HAT mechanisms:
O
W
O
N
N
Fe
N N N
Cyclohexane oxidation
(Que, J. Am. Chem. Soc. 2004, 472)
Ar
Ar
O
N
N Mn N
N
Ar F
O
O
O
O
W
O
O
O W
O
W O
O O W
O
O O
O O
W
O
O O
O W
O
W O
O
O
W
O
O O
O
O
W
O
Multiple HAT-initiated transformations
(Hill, Synlett 1995, 127)
O
Ar
Aliphatic C–H bond fluorination
(Groves, Science 2012, 3122)
Drug metabolism
(Cytochrome P450 enzymes)
Baran Group Meeting
4/12/14