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Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
S
S
S
S
TTFE1 = +0.32 VE2 = +0.71 V
NMe2
NMe2Me2N
Me2N
TDAEE1 = –0.78 VE2 = –0.61 V
N
N
N
N
Me MeMurphy
E1 = –0.82 VE2 = –0.76 V
MurphyE = –1.24 V
N
N
N
N
MurphyE = –1.20 V
NN
Me2N NMe2
Several reviews on OEDs as they pertain to organic synthesis have been recently published.
Comprehensive review: Vanelle, Angew. Chem. Int. Ed. 2014, 384Additional review: Murphy, "Organic Electron Donors." In Encyclopedia of Radicals in Chemistry, Biology, and MaterialsPerspective on super electron donors: Murphy, J. Org. Chem. 2014, 3731Perspective on super electron donors: Murphy, Chem. Commun. 2014, 6073
N
N
Me
Me
PhH
DMBIE = +0.33 V
N
N
Me
Me
1,4-DMPE = +0.89 V
N Me
Me Me
nPr3NE = +0.95 V
OEDs are typically electron rich alkenes, although there are some reports of aliphatic amines bearing weak OED properties. Shown below are some of the OEDs discussed along with their corresponding redox potentials (E) and typical parent substrates for a qualitative reference.
R–X [R–X]•– R• R–H
R–E+
R–E
D•+
R–D+
Nuc–
R–Nuc
D D•+ X–
HATSET
D•+ or D2+
D or1D•+1
SET
D
Organic electron donors (OEDs) are neutral, ground state organic molecules that reduce substrates by single electron transfer.
Reactions with OEDs thus involve the intermediacy of radicals, which can ultimately end up getting either reduced, converted into nucleophiles, or converted into electrophiles.
–3.5 E (V)
–3.0 –2.5 –2.0 –1.5 –1.0 –0.5 0.0 +0.5 1.0
MeBr MeI
Cl Br I +N2
1. Introduction
*Photoinduced electron transfer will be minimally covered, see "Photoinduced Electron Transfer in the Days of Yore," Yan 2014 group meeting for more.
Dr. William R. Dolbier, Jr.University of Florida
Dr. John A. MuphyUniversity of Strathclyde
Dr. Patrice VanelleAix-Marseille University
CBr4
Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
Similarly, solvent quantities of nPr3N could facilitate SET to fragment PhSSPh (Ishibashi, Org. Lett. 2009, 3298).
1,4-DMP was proposed to dehalogenate trichloroacetamides through an analogous pathway (Ishibashi, Tetrahedron Lett. 2008, 7771).
The reductive cleavage of halides from α-haloketones, esters, and acids using DBMI was initially believed to proceed via Sn2 displacement with a hydride (Chikashita, J. Org. Chem. 1986, 540).
N,N-dimethylaniline, benzylamine also facilitate facilitate similar reactions
N
N
Me
Me
PhH
N
N
Me
Me
PhH
N
N
Me
Me
Ph
Ph
OBr
Me
Br–
Ph
O
Me
N
N
Me
Me
PhH Ph
O
Me
H
Ph
OBr
MeN
N
Me
Me
Ph
Br–
However, later experiments supported the intermediacy of radicals and led to the proposal of a SET-initiated pathway (Tanner, J. Org. Chem. 1989, 3842).
Ph ClO
Me
Ph
O
Me
The addition of radical initiators/inhibitors altered yields ca. ±50%
DMBI
Also:
N
N
Me
Me
PhH
DMBI
Ph H
O
BrTHF, Δ(89%)
DMBIPh H
O
H
N CCl3
O
OAc
N
HH
OClCl
OAc1,4-DMP
(neat)133 °C(52%)
NN
Me
Me
1,4-DMP
Reaction can still proceed at 65 °C
DBU effects similar reactivity at rt
TsHN
PhSSPhnPr3N140 °C(68%)
TsHN
SPhO
Me
Me
O
PhSMe
MePhSSPh
nPr3N, H2O140 °C(45%)
2. Amines 3. Tetrathiafulvalene (TTF)
S
S
S
S
The first studies on TTF centered on its oxidation (Wudl, Chem. Commun. 1970, 1453).
S
S
S
S
S
S+
S
S
S
S+
+S
S
TTF facilitiated cyclizations of aryldiazonium salts via a radical-polar crossover mechanism (Murphy, J. Chem. Soc. Perkin Trans. 1 1995, 623).
Cl2CCl4
Cl2CCl4
TTF, yellow solid TTF•+, deep purple solid TTF 2+, yellow solid
O
R1
R2N2+
O
OHR2
R1
O
R1
R2
O
R2R1
O
SR2
R1 S
S S
O
R2R1
1a: R1 = R2 = H1b: R1 = Me, R2 = H
1c: R1 = R2 = Me
3a: R1 = R2 = H, (75%)
2b: R1 = Me, R2 = H, (73%)2c: R1 = R2 = Me, (58%)
ROH and MeCN could also be used as nucleophiles, but others (N3-, HO-, malonate) were unsuitable (Murphy, Chem. Commun. 1997, 1923).
O
S N3
S
S
S
S
(0.5 equiv)
+
O
S S
S S
NaN3, acetoneMech?
TTFacetone
H2O
+TTF•+
H2O
-TTF
TTFSET
-N2-TTF•+
The presence of heteroatom adjacent to the aryl group was required for termination by nucleophilic substitution (Murphy, Chem. Commun. 2000, 627).
S
OMe
Cy
N2+
S
OMe
CySRN1
S
OMe
S
SS
SSTTFacetone
H2O(48%) (32%)
+
-TTF•+
-N2
+
-MeOH +TTF•+
3a
Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
This was used in total synthesis of aspidospermine (Murphy, J. Chem. Soc. Perkin Trans. 1 1999, 995).
Radical translocations via a [1,5]-HAT were also demonstrated (Murphy, J. Chem. Soc. Perkin Trans. 1 1995, 1349).
NMsN2+
TTFacetone
H2O(45%)
NHCOCF3
NMs
NHCOCF3OH
H NMs
NHCOCF3O
H
Me
NMsH
Me
NCOCF3
NMsH
N
NH H
N
Me
aspidospermine
O
N
Me
Me
N2+ O
N
Me
MeHH
O
N
Me
MeH
O
NH
Me
H
TTFacetone
H2O
H2O
N O
Me
N2+ Me
Me
N O
Me
Me
Me
TTFacetone
H2O
(85%)
N OMe
S SS
+SMeMe
(53%)
N O
Me
Me
Me
TTF
(14%)
+
Bulking up the substitution around the TTF core led to a reduced rate of premature radical trapping with TTF•+ and its derivatives (Murphy, Tetrahedron Lett. 1997, 7635).
However, the DTDAFs were prone to rapid cleavage if DTDAF•+ trapped an intermediate radical (Murphy, J. Chem. Soc. Perkin Trans 1 1999, 3637).
N2+
O
O
PhS O
O
O
O
OH
PhS
+OED
acetoneH2O
S
S
S
SMe
Me Me
Me
S
N
N
SE
E E
E
Me
Me4 5
TMTTF4 (8%), 5 (67%)
DTDAF4 (0%), 5 (72%)
TTF4 (19%), 5 (48%)
S
S
S
S
N2+
O
Oacetone
H2O
DTDAFO
O
SN CHO
CO2MeCO2Me
(50%)Mech?
4. Tetrakis(dimethylamino)ethylene (TDAE)
F
F Cl
F excessMe2NH Me2N
Me2N NMe2
NMe2
"A small room can even be dimly lit for over an hour... with about 10 mL of TDAE."
OO
Me2N NMe2NMe2
NMe2
NMe2
NMe2NMe2Me2N
Me2N
O
NMe2(2 equiv)
"This was a clear, slightly yellow, mobile liquid which was strongly luminescent in contact with air."
TDAE had some illuminating properties (Pruett, J. Am. Chem. Soc. 1950, 3646).
-TDAE-hν
Can perform similar radical cyclizations to TTF, however, a leaving group typically needs to be incorporated into the substrate to terminate the reaction since TDAE•+ does not recombine with radical intermediates (Murphy, Beilstein J. Org. Chem. 2009, 1).
NMsN2+
BrTDAEDMF(74%) N
Ms
NMs
Br
NS
OO
N2+
TDAEacetoneMeOH
+NH
(33%)
NS
OO
(60%)
However, TDAE was initially used to dehalogenate polyhalogenated molecules with the more electropositive halogens being easier to remove (Carpenter, J. Org. Chem. 1965, 3082).
F3C
CF3Cl
Cl
ClCl ClF3C
Cl CF3
BrCCl3 –CCl3CHCl3
CCl4-BrCCl2–
CCl2TDAE2+TDAE +H+
-Cl–
BrCCl3–Br
TDAEpentane
17 hdecane15 min (31%)
(22%)
(97%)
-N2-TDAE•+ -Br•
Me
Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
TDAE was used to generate HetCF2–, which could add into aldehydes, ketones (Médebielle, J. Org. Chem. 1998, 5385), pyruvates, and thiocyanates (Médebielle, Synlett 2002, 1541 and Tetrahedron Lett. 2001, 3463).
It has been suggested that TDAE performs two sequential SETs to acceptor substrates to generate anions.
TDAEDMF
-20 °C to rtN CHON
NO
Ph
CF2Br(60%)
NN
O
Ph
OHF F
N+ Me
OEtO O
(ca. 55%for both)
S
NMe2
CN
R3C–XMe2N
Me2N NMe2
NMe2Me2N
Me2N NMe2
NMe2
XCR3
charge transfer complex
Me2N
Me2N NMe2
NMe2
CR3 –XTDAE
TDAE 2+
TDAE•+
SET~0 °C
Me2N
Me2N NMe2
NMe2–CR3 –X
+
+ +
-20 °C
Radical intermediates could be intercepted using dihydrofuran as a radical trap.
O
N Br
FF O
N
FF
O
BrO
N F
F
TDAE
TDAE•+
O
N
N
CCl3 N
N
OCl
Me
N
N Me
OCl
DMF-20 °C to rt
(60%)
TDAE2-MePh O via:
TDAE and Zn0 have similar reduction potentials, but offer different regioselectivities in vinylogous Reformatsky reactions (Zhu, Tetrahedron Lett. 2004, 3677). Sulfonimine electrophiles only gave modest selectivities (Zhu, Synlett 2006, 296).
(95%)(48%)
Br
F F
OBnCO2Et
Ph
O+TDAEDMF
-10 °C to rt
Zn0
DMF0 °C
Ph
OHCO2Et
OBn
F F
F
F
OBnCO2Et
OHPh
(Hetero)aryl difluorochloromethyl ketones could also be added into activated electrophiles such as aryl aldehydes, α-ketoesters, and thiocyanates (Médebielle, Tetrahedron Lett. 2008, 589; for more examples, see Dolbier J. Fluorine Chem. 2008, 930).
NN
CF2Cl
O
CF2ClO
Me MePhCHOTDAE
DMF-20 °C to rt
(60%)
N O
O
O
PhF
F F
OH
Ph
N O
O
Me2N
F F
O–
Ph
FF
Ph
O-Me2N–
-HF
Reductive cleavage of electron-deficient benzyl chlorides leads to adducts with α-halocarbonyl compounds and other electrophiles (Vanelle, Tetrahedron 2009, 6128).
O
O
NO2
N
O
O
(68%)
TDAEDMF
-20 °C to 70 °C
O
O
NO2
ClN
O
OBr+
Sometimes light was believed to completely change the reaction mechanism (Vanelle, Tetrahedron Lett. 2008, 1016).
OMe
OMeMe
Me
Me
Cl4-NO2Ph O
no reactionno hν
hν(82%)
TDAE, DMF-20 °C to rt
OMe
OMeMe
Me
Me
O 4-NO2Ph
O
R
O
R
O
OMe
OMeMe
Me
Me
O R
O2Proposed SET to aldehyde:
R
O Ar ClTDAEhν
Irraditation could increase yields in certain cases, but it altered the reaction outcome in other ones (Vanelle, Eur. J. Med. Chem. 2010, 840).
N
NS
NO2
Cl
O
CO2EtN
NS
NO2
HOCO2Et
+ N
NS
NO2
CO2Et
no hν hν48 h
(77%)2h
(51%)from spontaneous E1 cb?
The initial products of the anionic additions could also undergo rearrangements (Vanelle, Tetrahedron Lett. 2006, 6573).
SET
Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
TDAE can reduce CF3I to CF3–, which adds into various electrophiles (Dolbier, Org. Lett. 2001, 4271 and J. Fluorine Chem. 2008, 930).
N SS N
(200% based on disulfide)
TDAE (2.2 equiv)CF3I (5 equiv)
N
SCF3
DMF0 °C to rt
The CF3– could also be added into disulfides and diselenides (Dolbier, Org. Lett. 2004, 301).CF3–
RS–SR
RSCF3 RS–
CF3IRSCF3
+
(Het)Ar R
O
R = H or Ph (68–95%)
TDAE (2.2 equiv)CF3I (2.2 equiv)
DMF, hν-20 °C to rt
(Het)Ar R
CF3HOAr Cl
O
(48–98%)
OS
O
OO
alkyl(ca. 50% after
hydrolysis)(ca. 70%,
ca. 85:15 dr)
Ar
N
H
S p-tol
Ono hν required:
BrBr
TDAEcat. I2
Reductive debromination in the presence of dienophiles can lead to the formation of Diels-Alder adducts (Nishiyama, Tetrahedron Lett. 2005, 867).
α-Bromoketones and esters could be dimerized using TDAE (Nishiyama, Tetrahedron Lett. 2006, 5565). Dithianyliums also underwent dimerization (Kirsch, J. Fluorine Chem. 2004, 1025).
CO2Me
Me
CO2Et
CO2Et
TDAE can reduce (CF3S)2 to form a complex that can be used as a CF3S– source (Kolomeitsev, J. Chem. Soc. Perkin Trans. 1 2000, 2183).
Me CO2Me
EtO2C CO2Et
(32%)
(51%)
THF67 °C
Ph
OBr
TDAEcat. I2
MgSO4THF, 67 °C (94%)
Ph
OPh
O
S S+
4-FPh (91%)
4-FPh 4-FPhS S
SSTDAEMeCN
-15 °C to rt
TDAEDME
-20 °C to rt
F3CS SCF3
2CF3S- N
SCF3
DMF, MeCN0 °C to rt
PhCH2Cl orpyridine
(98%) (80%)NMe2
NMe2
NMe2Me2N or
(95%)
SCF3
TDAE can be used as a reductant for transition metals, as demonstrated by the Pd-catalyzed oxidative dimerization of (hetero)aryl bromides (Tanaka, J. Org. Chem. 2003, 3938).
TDAE can also be used for NHK reactions substoichiometric in Cr (Tanaka, Synlett 1999, 1930 and Tetrahedron Lett. 2000, 81).
OHC
Br cat. PdCl2(PhCN)2TDAE (2 equiv)
DMF, 50 °C(88%)
OHC CHO
OHC
PdIIBr
OHC
Pd0-1TDAE
TDAE2+
Pd0
Ar—Br
Little is known about the redox chemistry of species like 6, but they can cleave P–Cl bonds to form radicals (Goldwhite, J. Organomet. Chem. 1986, 21).
Under irradiation, similar donors could reduce Ar3SiCl, Ar3GeCl, and Ar3SnCl to Ar3M• (Lappert, J. Organomet. Chem. 1980, 5).
PP P
P
tBu
tBu tBu
tBu
P CltBu
Cl
P ClPh
Ph P PPh
PhPh
Ph
P ClAr
ClAr = 2,4,6-tri(tBu)Ph
6(1 equiv)
PP
Ar Cl
ArCl
PP
Ar
Ar(88%)
(57%)
quant.
Si Mes
Mes
Mes
Mes Si Cl
MesMes
ESR only
A few other aliphatic tetraaminoethylenes are known, but most exist as their NHC monomers.
N
N
N
NR R
RRN
NR
RN
N
N
NEt Et
EtEt
Exception when R = Me or Et:
6
quant.
6
6
6(excess)
stronglyfavored
N
N
N
NMe Me
MeMe
+hν
5. Bisimidazolidinylidenes
Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
6. Tetraazafulvalenes (TAFs)
N
N
N
N
Me MeN
N
N
N
Me MeN
N
N
N
Me Me–1.21 V –1.31 V –1.44 V
Early studies on the redox potentials of bisimidazolium salts supported the notion that introducing unsaturation into the rings of cyclic tetraaminoethylenes would result in strong OEDs (see Vanelle, Angew. Chem. Int. Ed. 2014, 384).
aromatic nonaromatic
N
N
N
N
Me MeN
N
N
N
Me MeN
N
N
N
Me Me
+e–
-e–
+e–
-e–
Less planar salts were harder to reduce (shown with corresponding E in MeCN vs SCE):
The TAF giving this dication would have the highest reduction potential
N
N
N
N
Me Me
2 I–
N
N
N
N
Me Me
KHMDSPhMeDMF
I2
7
N
N
N
N
Me Me
2 I–
The earliest TAFs contained methylene bridges, which were essential in keeping the two NHC halves dimerized (Murphy, Angew. Chem. Int. Ed. 2005, 1356).
TAF 8 proved to be strong enough to reduce aryl iodides, which were previously unable to be reduced by OEDs, making it the first "super electron donor" (SED).
7, KHMDSDMF, rt;
NMs
OMeI
substratePhMe, Δ N
Ms
OMe
(90%)
NMs
NMs
OMe
NMs
OMe
NMs
OMe
not observed
HAT -MeO–
+e–
Although 8 was unable to perform a second SET to form aryl anions, a more powerful SED was identified that could (Murphy, Angew. Chem. Int. Ed. 2007, 5178).
2 I–
N
N
N
N NaH
NH3(l)(98%)
N
N
N
N I I
MeCN, Δ0.003 M24 days
109, (51%)
N
N
N
N
N
N
N
N2 e–2 X–
Cyclization supported the formation of an aryl anion, as aryl radicals do not add into esters. Even polycyclic aryl bromides and chlorides could be reduced with 10.
Unfortunately, much like with TTF, 10•+ could trap intermediate alkyl radicals and hydrolyze, resulting in the formylation (Murphy, J. Am. Chem. Soc. 2009, 6475).
9, NaHDMF, rt;substrateDMF, Δ(86%)
O
CO2EtI
MeMe
O MeMe
O
(51%) (21%)O
CO2EtH
MeMe
10
DMF100 °C
+
Br H 9, NaHDMF, rt;substrateDMF, Δ(99%)
Cl H
N
N
N
N
RN
N
N
N
R
N
N
N
N
R
HH
O
ROH
O
H
OR -CO2
N
N
N
N
R
NMs
I
NMs
CHOMe Me
no deuterationwith d7-DMF
PhO Br6
PhO CHO6
9, NaHDMF, rt;
substrate;HCl workup
9, NaHDMF, rt;
substrate;HCl workup
(13%)Proposed mechanism:
N
N
N
N
CH2R
-H+
+H+
11
Evidence against SET pathway involving 11:
NMe
MeN
RHO
O
R H
O
R
abovecond.
not formed
8(61%)
10•+
H3O+
(2%)
+e–
-I–
Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
Reductive cleavage of SO2Ph group from (di)sulfones and sulfonamides was possible with 10 (Murphy, J. Am. Chem. Soc. 2007, 13368).
SO2PhPhO2S HPhO2S
(96%)
9, NaHDMF, rt;substrate
DMF, 110 °CNTs
9, NaHDMF, rt;substrate
DMF, 110 °CNH
(91%)
Proposed mechanism (later radical clock experiments suggested fragmentation to form aminyl radicals is favored in the case of sulfonamides):
XArO2SR1
R2XArO2S
R1
R2
X–SO2ArR1
R2+
–XSO2ArR1
R2+
+e– +e–
+H+X
R1
R2H
+e–
Attempts to prepare analogs of 10 showed that its double methylene bridge was essential for stability (Chen, Angew. Chem. Int. Ed. Engl. 1996, 1011).
N
N
N
N
Me MeN
N
N
N
Me Menot isolated isolated
However, it was found that mono- and even untethered species could be generated in situ that showed SED reactivity (Murphy, Chem. Sci. 2012, 1675).
N
N
N
N
N
N
N
N
not isolated isolated
N
N
N
N
Me Me
Me Me
N
N
N
N
Me Me
NaHDMF
OI
Ph
OH
Ph(79%)
2 I–
N
N
N
N
Me Me
NaHDMF (61%)N
NMe
Me
I–
"even a surface hydroxyl group on glass could catalyze [the decomposition of these TAFs]"
7. Bispyridinylidenes
It could even do some things that other SEDs couldn't (Murphy, Synlett 2008, 2132).
NN
Me2N NMe2
The previous SEDs were not amenable to analog production, but similar SED synthesis strategies could be used to generate different scaffolds (Murphy, Org. Lett. 2008, 1227).
NN
Me2N NMe2
NN
Me2N NMe2
2 I–
NaHNH3(l)
I –
(83%)
13
Bispyridinylidene 13 could do everything that the other SEDs could do, but better and had the advantage of being more "bottleable."
tBuI
tBu
tBu
O
CO2EtI
MeMe
O MeMe
O
DMF, rt(D2O)(95%)
tBuH/D
tBu
tBu
R
O
NOMe
Me R
O
NOMe
Me R
O
NOMe
Me
-MeO–
R
O
N MeR
O
N MeR
O
NH
Me
O
NOMe
MePh
O
NH
MePh
12
12, NaHDMF;
substrate(94%)
O
NH
MePh
100 °C, (77%)
O
NH
Me
5 equiv 12, 100 °C, (43%)
Me
O
NH
Me
(81%)N
SET
SET+H+
Proposed mechanism:
Similarly, acyloin derivatives could be deoxygenated by 13 (Murphy, J. Org. Chem. 2009, 8713).
Ph PhO
ORPh Ph
O
H
12, NaHDMF;
substrateR = Ms, (93%)R = Ac, (98%)R = Piv, (97%)
Ph
OO Me
OMe MeO
Ph
O
Me Me
13(1.5 eq)
DMF, rt(95%)
13(1.5 eq)
Basicity occasionally problematic
12, NaHDMF;
substrate(86%)
Organic Electron DonorsJulian LoBaran Group Meeting
1/10/15
S–O (instead of C–O) bond cleavage of alkyl triflates was also possible (Murphy, Org. Biomol. Chem. 2012, 5807).
Once again, photoactivation (UV) of these SEDs enhances their strength (Murphy, Angew. Chem. Int. Ed. 2012, 3673)...
It was found that benzyl esters, ethers, and sulfonamides could be debenzylated by this approach (Murphy, Angew. Chem. Int. Ed. 2013, 2239 and Angew. Chem. Int. Ed. 2014, 474).
OTf
Br
18O-DMF labeling disproved a pathway invoking C–O bond cleavage by DMF
(84%)
DMF(91%)
OTf
Ph
13 OH
Ph
N BnPh
Tf3 equiv 13
100°C, (40%)
OR
H
Me2N+ ORMe2N
H OH
ROH
SET;HAT
ORMe2N
H H
H2O
H2O
H2O
R OTf18O-DMF
not observed!
Which even allows for SET to ground state benzenes, raising the possibility of a future OED Birch-type reduction.
no hν, 100 °C (0%)with hν, rt (87%)
13 (3 equiv), DMFCl
O
PhH
O
Ph
cis:trans 98:2
(6%)
+e–cis:trans 70:30
(66%)13, hν
O
O
nBu
Et
OMe
HO
O
nBu
Et
O Me
Me
Me
OMe13 (6 equiv)
hν, DMF, 72 h(73%)
13 (3 equiv)hν, DMF, 24 h
(91%)
Me
MeMe
HO
N
OMe
MeO
MsCy
NH
MsCy
13 (6 equiv)hν, DMF, 72 h
(80%)
Additionallly, π-stacking interactions between 13 and aryl groups in the substrates can lead to chemoselectivities opposite of conventional reagents (Murphy, J. Am. Chem. Soc. 2013, 10934).
Ph
CO2EtCO2Et
Ph
CO2EtNa0
or K0
OOEt
Ph
CO2Et
O OEtPh
CO2EtH
Ph
CO2EtCO2Et
Ph CO2Et
CO2Et
H
Ph
CO2EtCO2Et
13, hνDMF
+H+ +H+
(75%)
-e–
