Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0909 110

17. Syntheses and uses of isotopically labelled compounds

1019

H

OH + B:

−

OH +

+

k′

H

N

C

H

N

C

BH

slow

H N C

fast

+ H2 O +

B

k ′ = Kc Kw / Ka (Kw = dissociation constant of water, Ka = dissociation constant

of α-aminoalcohol as acid)	(189)

the reaction of the electrophile with an intermediate, suggested to be the enol tautomer (equation 191 193), the substrate kinetic isotope effect ke H/ ke D of 2.30 and 2.20 for CD2(COND2)2 and values of the solvent isotope effect ke H2O/ ke D2O of 1.09 and 1.05 have been observed386 for iodination under zero-order conditions, when enolisation is rate-limiting. In the absence of mineral acid the disappearance of resonance of the methylene proton NMR at υ 5.7 was 80% complete in one day. In the presence of D2SO4 the H/D exchange was 89% complete in 5 min and 96% complete in 12 min (at 25 °C). The KIE of 2.2 2.3 found in enolization of MA, when methylene protons were replaced by deuterium, is significantly smaller than the value kH/kD D 6.7 found for acetone enolization387. Maximum isotope effects are expected to occur when pK 0, and are smaller for both the ‘early’ and the ‘late’ TS. The greater acidity of the protons in MA than in acetone should be responsible for the observed difference in KIE. Kinetic solvent isotope effects387 389, kH2O/kD2O, are usually around 0.5.

HC

CH2(CONH2)2 C HNO2 ! HONDC CONH2 2 C H2O

190

MA

ke[HC ]

Enol

191

k

Enol C I2 ! Product

192

fast

H2 O, slow

C

CH + H3 O+

C

C

C

C +

H2 O

(193)

OH+

O

HO

The near-unity values of 1.09 and 1.05 for enolisation of MA in (H2SO4

H2O)/(D2SO4

D2O)

and DMA (deuteriated

malonamide, CD2(COND2)2) in

(H2SO4

H2O)/

(D2SO4

D2O) are explained by assuming that the normal (i.e. about 0.5) IE is offset

by the isotope effect in intramolecular hydrogen-bonding shown in equation 194.

NH2

O

+

+

CH2 +

(194)

CH2 (CONH2 )2 + H3 O(D3 O)

H(D)

+ H2 O(D2 O)

O

NH2

5. Aqueous diazene and its dismutation in fully deuteriated medium

Aqueous 1,2-diazene, N2H2, the optically detected intermediate in the acid-assisted hydrolysis of azodiformate (equation 195), believed to be also an intermediate in certain

1020	Mieczysław Ziełinski´ and Marianna Kanska´

oxidations of hydrazine390,391, undergoes a second-order concerted dismutation on a time scale longer than that of its generation when the hydrolysis is conducted392 at pH ³ 4 (equation 196). The overall DKIE, k1 H /k1 D , when the dismutation reaction (equation 196) has been conducted in fully deuteriated medium, was 3.3 š 0.5. This value (sum of the primary, secondary and solvent IEs) is consistent with a significant degree of hydrogen atom transfer in the TS. A two-step mechanism of decay of aqueous diazene has been proposed (equation 197 and 198).

			fast
NCO2 2 C 2HC ! N2H2 C 2CO2								195
		k1						196
		2N2H2 ! N2 C N2H4
trans		N2H2	cis		N2H2 k trans cis			197
					k 2H
cis N2H2 C trans N2H2 ! N2 C N2H4								198

In the rapid pre-equilibrium the high-energy cis-isomer is formed, and double hydrogen atom transfer takes place in the last step. It is likely that the value KIE D 3.3 will be typical of other hydrogenations by diazene392.

6. Deuterium isotope effects in the reactions of 2-nitroso-2-methyl propane with formaldehyde, glyoxylate, glyoxylic acid, pyruvic and phenylglyoxylic acid

All the title reactions, involving the dipolar addition intermediates (equation 199), yield the corresponding N-t-butyl hydroxamic acids393. The aliphatic C-nitroso group acts as nucleophile in the reaction steps leading to the formation of these intermediates. The inverse solvent deuterium isotope effect (kD2O/kH2O) of 2.02 observed in the reaction of 359 with formaldehyde, 354, producing N-t-butyl formohydroxamic acid, is interpreted as arising in the reversible equilibrium proton transfer to the intermediate 360. The primary kinetic isotope effect (kH/kD) of 4.52 for HCHO and DCDO used in reaction 199 is consistent394 with a rate-controlling proton transfer from carbon of the nitrosocarbinolic intermediate 361 leading to hydroxamic acid 362.

The solvent deuterium isotope effect in the reaction of 359 with glyoxylate decreases from (kH2O/kD2O) of 1.66 to (kH2O/kD2O) of 1.17 with increasing pH from 1.25 to 6.43, respectively. 361 probably decarboxylates via a cyclic transition state. Transfer of the carboxylic proton takes place simultaneously with heavy-atom reorganization as indicated by small solvent DIE in the acid-catalysed reaction. The solvent DIE kH2O/kD2O of 1.20

at 1. M HC , observed in the reaction of 359 with pyruvic acid, is similar to the reaction of pyruvic acid with nitrosobenzene for which nucleophilic attack of nitroso nitrogen has been proposed395.

7. Deuterium KIE in the metalation of imines by lithium diisopropylamide

The deuteriated (97%) imines 363 and 365, and the hydrazone 364 have been prepared396 399 by treating 2,6,6-trideuterio-2-methylcyclohexanone and 2,2,6,6- tetradeuteriocyclohexanone with the corresponding deuteriated ammonium salts (RND3Cl) and used in the KIE studies of the metalation of the above ‘CDN’ compounds with lithium diisopropylamide (LDA) in THF, in N, N, N0, N0-tetramethyl ethylenediamine (TMEDA) and in dimethylethylamine (DMEA) solvents (equation 200). The rates, d[imine]/dt of that of imines 363 and 364 metalation are zero order with respect to [THF], [TMEDA]

17. Syntheses and uses of isotopically labelled compounds

1021

and [DMEA] concentrations in hexane, 1/2 order with respect to [LDA] and first order with respect to [imine] (equation 201).

O

O−

Bu-t

R1

R2 + Me3 C

R1

+

C

N

O

C N

O

R2

(359)

(360)

H+

OH	Bu-t		O	OH
	+
R1 C	N		C	N
R2	O		R1	Bu-t

		(361)				(362)
(354)	R1	= R2 = H		(357)	R1	= Me, R2 = COOH
(355)	R1	= H, R2	= COO−	(358)	R1	= Ph, R2 = COOH
(356)	R1	= H, R2	= COOH

R		Li	R
N			N
Me	LDA /donor solvent	Me
	20°C (or 0.0°C)

d[imine]/dt D k0 [imine] [LDA]1/2[TMEDA]0

	CH(Me)2			NMe2
	N			N
D2 C	CD2	Me
			CD	CD2
H2 C	CH2		H2 C	CH2
	CH2			CH2
(363) k / k (temp. °C, solvent)		(364) k	/ k (temp. °C, solvent)
H	D	H	D
11.2 ± 2.0	(20°C, THF / hexane)	6.4 ± 0.6	(0.0	°C,THF / hexane)
6.2 ± 1.2 (20°C, TMEDA / hexane)		8.3 ± 1.2 (0.0		°C, TMEDA)
7.7 ± 1.0 (20°C, DMEA / hexane)		6.9 ± 1.8 (0.0		°C, DMEA)
		(rapid metallation at 20˚ C)

(199)

(200)

201

1022	Mieczysław Ziełinski´ and Marianna Kanska´
		CHMeCH2 NMe2
		N
	Me
	CD	CD2
	H2 C	CH2
		CH2
(365) kH / kD (temp. °C, solvent)
>5	(0.0° C,THF/hexane), very slow reaction

2.0 ± 0.1(0.0° C, TMEDA)

2.3 ± 0.1(0.0° C, DMEA)

Metallation rates determined by monitoring the loss of the C N stretch of the starting imine (1656 − 1660 cm−1) were comparable (±10%) with rates determined by monitoring product formation (1590 − 1600 cm−1)

In the case of imine 365, an inverse second-order dependence on [TMEDA] and [DMEA] has been observed (equation 202).

d[imine]/dt D k00 [imine] [LDA] [TMEDA] 2

202

A suggestion has been made397 that 364 and 363 are metallated by monomer-based mechanisms shown in equation 203.

						R2
		S			N
								R1
i-Pr		Li		Pr-i	R1			N R2
1/2	N		N		+			Li S
i-Pr		Li		Pr-i				N(Pr-i)
								2
								(368) intermediates
		S
					R2			transiently formed monomers
					N
					R1

(369)	(203)

Metallation of 365 in THF/hexane mixtures is also described by rate equation 201, but that of 365 (‘bearing pendant Me2N moieties’) in TMEDA and DMEA, described by rate equation 202, suggests a mechanism involving rate-limiting metallation via dimeric LDA dimer stripped free of donor solvents, shown in equation 204.

These problems have been discussed extensively, reviewed and a conclusion has been reached that the proton abstraction in intermediate 366 leading to 367 proceeds through the ‘optimal’ eight-membered transition structure ring size397. The values of deuterium

17. Syntheses and uses of isotopically labelled compounds

1023

KIEs shown under structures 363, 364 and 365 clearly indicate that the rupture of the C 6 D bonds are involved in the metallation of 363 and of 364 in the rate-determining step and the TS structure shown in equation 203 is a symmetric one. The kH/kD value of 11.2 š 2.0 observed at 20 °C in the metallation of 363 in THF/hexane mixture suggests that the transfer of proton from the C 6 H bond to nitrogen of the solvated lithium diisopropylamide in 368 is accompanied by tunneling. The kH/kD values of 2.0 observed at 0.0 °C in TMEDA/hexane and in DMEA/hexane solvents (2.3 at 0.0 °C) in the lithiation of 365 with solvent-free LDA dimer are characteristic for asymmetric TS in hydrogen abstraction-transfer processes. The detailed timing of bond changes in 366 leading to 367 is a KIE computational problem as well as an experimental one to be solved and completed.

Me

NMe2

S

N

i-Pr

Li

Pr-i

N

N

i-Pr

Pr-i

i-Pr

Pr-i

Li

R

Li

N

N

+

−2S

NMe2

i-Pr

Li

Pr-i

N

S

Me

R

R

Me

(366) open dimer

Li

N

(204)

Me

N

Me

(367)

8. Inverse deuterium KIEs in the bromination of perdeuteriated 7-norbornylidene-70- norborane 370

Large inverse DKIE have been observed400 in the reaction402 of 370 and 371 with Br2 in AcOH and MeOH at 25 °C in the presence of LiBr, and explained by a pronounced steric DKIE401,403 on the partitioning of a reversibly formed bromonium ion 372. There is less compression of the endo C-L groups in the rate-limiting TS for electrophilic addition to 371 (D20 species) than to 370 (H20 species).

In AcOH, the DKIE increase from 1.53 (at M D 0.1 LiClO4) at zero added [Br ] to 2.75 at [Br ] D 0.05 M. In MeOH, the inverse DKIE is practically independent of the added [Br ] and equal to 1.85 š 0.15. In AcOH, the amount of dibromide product increases up to 82.6 5 with increasing [Br ] to 0.05 M. In MeOH, the methoxy bromide is the prominent product400 even at the highest [Br ].

The inductive effect of the donating C D bonds to the observed large inverse secondary deuterium isotope effect has not been given proper consideration but treated as a rather minor component superimposed on the important steric component caused by larger amplitudes of vibrations of C H bonds than those of the C D bonds. 14C KIE have not been studied in this reaction. The C2, C2‘, C3‘, C3, endo hydrogens are separated only by 2.11 A,˚ substantially less than van der Waals radii 2 ð 1.2 A˚ 404.

1024	Mieczysław Ziełinski´ and Marianna Kanska´
			5			5′
	R10	4		6	6′	4′	R10
	3				7′ 1′		3′
			1	7
		2				2′
			(370)	R = H, (371) R = D
		L	L		Br+	L	L
	L		L			L		L
	L		1			1′			L
		L					L
	L 2	L					L	2′	L
					(372)
9. Secondary ˇ-tritium IEs in elimination reactions
The secondary	tritium,	H/T	and D/T		IEs in	E2 reactions		of	RNMe3C Br , where

R D p-CF3PhCLTCH2, 373, L D H or D; R D PhCHCL2T, 374, L D H or D;

p

-ClPhCLTCHPh, 375, L D

H or D, defined in the case of 373 by equations 205,

R D

405

in the temperature interval 29.60

74.00 °C.

206 and 207, have been determined

ArCL2CH2X C RO

2k1

205

! ArCLDCH2 C ROL C X

k2

ArCL

CH2

+ ROT +

X−

(206)

ArCLTCH2

X + RO−

k3

+ ROL +

X−

(207)

ArCT

CH2

When LDH, k1/k3 D HkH/TkH, and when L D D, k1/k3 D DkD/TkD, the subscript represents the transferred atom, the superscript represents the atom remaining behind. The

k1/k3 values have been determined by comparing the activity of the product olefin at the beginning of the reaction, Rs0, with the activity of the quaternary ammonium salt, R0. Equation 208 has been used for calculating the IE in the reaction of 373 and equation 209

in the case of compound 374, which has three reactive hydrogens.
k1/k3 D 0.5R0/Rs0	208
k1/k3 D 2R0/3Rs0	209

In the reaction of 373 with EtO /EtOH as the base/solvent system, the ratios HkH/TkH have been found to equal (at temperatures given in parentheses): 1.332 š 0.009 (at 29.60 °C), 1.293 š 0.008 (at 40.00 °C), 1.266 š 0.013 (at 50.20 °C), 1.25 š 0.006 (at 60.00 °C) and 1.209š0.003 (at 69.80 °C). In the case of elimination reaction of 374 with t- BuO /t-BuOH, the HkH/TkH values are equal to 1.252š0.004 (at 35.50 °C), 1.238š0.004 (at 44.95 °C), 1.224 š 0.005 (at 54 °C), 1.223 š 0.004 (at 54.80 °C), 1.217 š 0.004 (at 65.05 °C) and 1.206 š 0.006 (at 74.00 °C).

17. Syntheses and uses of isotopically labelled compounds

1025

In

the reaction of 375 with EtO /EtOH the corresponding HkH/TkH values are:

1.271

š 0.006

(at 29.9 °C), 1.258 š 0.003 (at 40.35°), 1.238 š 0.004 (at

50.00 °C),

.

.

°

.206

0.008 (at 70.20 °C).

3

2

1 228

š 0 003 (at 60.40

C) and 1 H

šT

to sp

rehybridization at

The equilibrium isotope effect,

KH/ KH, for complete sp

the isotopically substituted position has been assessed406,407 to be 1.17 at 50 °C.

The secondary HkH/TkH KIE in the eliminations of 373, 374 and 375 presented above which are higher than this maximum possible secondary IE value, are taken as strongly implicating tunnelling. This conclusion has been supported also by intercomparison of secondary H/T and D/T isotope effects in E2 reactions of RNM3CBr at 50 °C. The secondary IE is depressed markedly when deuterium rather than proton is transferred,

which also implicates tunnelling:
Lk /Tk	D	1.267	š	0.012 (for L	H)	in reaction of 373 with EtO /EtOH
L L		1.032		0.003 (for L	D D)
	D		š		D
	D	1.224	š	0.005 (for L	H)	in reaction of 374 with t-BuO /t-BuOH
		1.029		0.003 (for L	D D)
	D		š		D
	D	1.238	š	0.004 (for L	H)	in reaction of 375 with EtO /EtOH
		1.031		0.003 (for L	D D)
	D		š		D

In the absence of tunnelling the value of the exponent R in relation408 210 equals 3.26:

kH/kT D kD/kT R

210

In this study405, HkH/TkH > DkD/TkD 3.26 and the value of relation 210 is satisfied for the exponent R of 7.0 7.5 š 0.1 in accord with significant tunnelling. The low values of the Arrhenius parameters AaH/AaT D 0.602 š 0.026 and EArhT EArhH D 0.478š0.028 kcal mol 1 found in reaction with 373 also support the above conclusion409. The carbanion-like TS in the E2 reaction of 373 favours tunnelling greatly.

10. Carbon-14C and deuterium KIE in the reductions of benzophenone with NaBH4, LiAlH4 and LiBH4

Carbon-14 and deuterium KIE in the reduction with benzophenone, determined at 25 °C, are listed in Table 1. The 14C KIEs are greater for SBH reduction than for LAH; the deuterium KIEs are normal for LAH and inverse for SBH. These results suggest a product like TS, 376, for the SBH reduction. In the course of the reductions the configuration at

TABLE 1. KIE	in the reduction of	benzophenone at
25.0 š 0.1 C.
Reagent/solvent	k12/k14 (av.)	kH4/kD4
	1.024 š 0.003		a
LiAlH4/Et2O		1.10	š 0.01b
LiBH4/Et2O	1.043 š 0.007	1.09	š 0.03a
NaBH4/l-PrOH	1.066 š 0.004	0.72	š 0.03	c
		0.77	š 0.001

a Determined by GC/MS, bDetermined by NMR. cThe ratio of the second-order rate constants for the protio and deuterio runs

are kH D 2.23 š 0.05 ð 10 3 dm3 mol 1 s 1 (NaBH4), kD D2.90 š 0.05 ð 10 3 dm3 mol 1 s 1 (NaBD4).

1026	Mieczysław Ziełinski´ and Marianna Kanska´

the metallation site changes from tetrahedral to planar, while the configuration at the carbonyl carbon changes from planar to tetrahedral when the bond order, nCH, of the newly formed C H bond increases from 0 to 1. The detailed calculation of 14C and D KIEs, neglecting the interaction of ROH solvent molecules in the TS with carbonyl oxygen and with boron atom, respectively, have been carried out410,411 for the model and its geometrical parameters shown in structure 376. In the reduction of benzophenone with LAH the simultaneous matching of calculated D4 and 14C KIEs with the experimental values was achieved when nCH D 0.35, that is for a reactant-like TS. Similar matching was achieved for the SBH reduction when nCH D 0.75 (product-like TS). The extent of hydride transfer from B to carbonyl carbon in the LBH reduction was determined as 0.55nCH.

H H

M

H

Θ1 H nMH

	Θ2	nCH
	C C
	C	O
		nCO
		(376)

nMH = 1.0 − nCH, nCO = 2.0 − nCH,

nCC = 1 − 0.1nCH, Θ1 = 120.0 − 10.5nCH, Θ2 = 90.0 + 19.5nCH, M = Al or B

11. Carbonyl-14C KIE in the reactions of ketones with organolithium reagents

The following carbon-14 kinetic isotope effects have been observed in the reactions of labelled ketones with MeLi and Me2CuLi providing the corresponding tertiary alcohols412 (equations 211 213):

Ph214CDO C MeLi : k12/k14 D 1.000 š 0.0002	211
D 0.27 š 0.07
Ph1214CDO C Me2CuLi : k12/k14 D 1.029 š 0.005	212
D 1.96 š 0.12
2,4,6-Me3C6H214COPh C MeLi : k12/k14 D 1.023 š 0.004	213

The above data have been rationalized in terms of the mechanisms shown in equation 214, and taken as indicating that reaction 211 proceeds via rate-determining electron transfer (ET), while in reactions 212 and 213 the rate-determining step shifts to recombination (RC) because in reaction 213 the RC-step becomes slower for the more hindered ketone. The small D 0.27 value in reaction 211 also means that the extent of the geometrical changes is negligible in the TS of this reaction. These qualitative interpretations of the 14C KIE have not been supported by model calculations as has been done similarly in the reactions of ketones with SBH and LAH. The 14CH3Li-carbon-14 KIE have not been studied in reactions 211 213. The inverse 14C KIE is expected in

17. Syntheses and uses of isotopically labelled compounds

1027

14CH3-KIE governed by transformation of the weak covalent 14C Li bond into a more covalent 14C 12C bond in the TS leading to tertiary alcohols.

						Me			Me
		O + MeLi		kPL
Ph C						Ph2 COLi			Ph2 COH		(214)
2
		kE T		O−	MeLi+	kRC		(PL = polar mech.)
			Ph2 C

It has been found412 414 that there are no carbon-14 KIE in the reaction of benzophenone with MeLi, while there is a large KIE (of 1.056) in the addition reaction of MeMgI, and that the reaction of benzophenone with alkyl magnesium bromide proceeds with a carbonyl 14C KIE of unity. The very small (close to unity) carbonyl-14C KIEs have been determined at 0.0 °C in additions of PhLi and allylithium to benzophenone and benzaldehyde415 (equation 215 217) and a general conclusion has been reached that all the reactions of aromatic carbonyl compounds with RLi studied proceed via the same mechanism, in which the rate-determining step is the initial ET step, followed by a subsequent fast step (equation 218). In no case are there any bonding changes at the carbonyl carbon in the rate-determining TS of these reactions415.

	Ph2CO C PhLi (in c-hexane/Et2O, 7/3), k12/k14 D 1.003 š 0.001							215
	Ph2CO C CH2DCHCH2Li(in Et2O), k12/k14 D 0.994 š 0.003							216
	PhCHO C PhLi (in c-hexane/Et2O, 7/3), k12/k14 D 0.998 š 0.003							217
							− +
	C O + RM	ET					OM	(218)
						RC
			C O, RM
							C

R

12. Carbonyl-14C KIE in the reactions of bezophenone-7-14C with various Grignard reagents

The mechanism of the Grignard reaction has been studied for many years416 418 and the sequence shown in equation 219 has been proposed417. The 14C KIEs in the reactions of benzophenone with various Grignard reagents, listed in Table 2, have been determined419 to identify the rate-determining step. The large 14C KIEs found in reactions with MeMgX, ArMgBr, and PhCH2MgBr have been interpreted as an indication of C C bond formation in the rate-determining step; the 14C KIE of unity (and a near-zero value, and no steric retardation) observed for allylic reagents has been taken as evidence of the initial SET rate-determining step (equation 219). Small 14C KIE, large value and no steric rate retardation observed in the Grignard reaction with t-BuMgCl are reported as indication of another route in which the isomerization of the radical ion-pair intermediate is the rate-determining step.

O + RMgX

SET

−

+

Ph2 C OMgX + R

Ph2 C

Ph2 C

O

RMgX

1,2-adduct

1,4-, 1,6-adducts

pinacol

SET = single electron transfer

(219)

1028	Mieczysław Ziełinski´ and Marianna Kanska´
	TABLE 2. Carbon-14 KIEs in the reaction of Ph2CO with various
	Grignard reagents
	Reagent/solvent		k12/k14		Value
	MeMgI/Et2O		1.056 š 0.002		0.54 š 0.16
	MeMgBr/Et2O		1.050 š 0.011		0.90 š 0.11
	MeMgBr/THF		1.056 š 0.004
	PhMgBr/Et2O		1.056 š 0.004		0.59 š 1.10
	o-MeC6H4MgBr/Et2O		1.060 š 0.014
	PhCH2MgBr/Et2O		1.024 š 0.007		0.02 š 0.09
	CH2DCHCH2MgBr/Et2O		0.999 š 0.002
	MeCHDCHCH2MgBr/Et2O		0.999 š 0.002		0.01 še0.03
	t-BuMgCl/Et2Oa		1.010	š 0.007	3.0
	t-BuMgCl/Et2O	b	1.004	š 0.004c
	MeMgI C FeCl3/Et2O		1.063	š 0.003d
			0.997	š 0.019

aDifferent batches of ketone and solvent were used. b5 mol% FeCl3 added.

cFor 1,2-adduct formation. dFor pinacol formation.

eTaken from reference 420

13.Carbonyl-14C KIE in Zn-promoted Barbier-type reactions

Two possible reaction pathways have been proposed421 for the Barbler-type carbonyl addition (equation 220): the polar (PL) route and the electron transfer radical coupling (ET RC) sequences with rate-determining ET or rate-determining RC (equation 221).

R2

R2

R1CHO + R2 CH

CHCH2 I

metal

R1CHCHCH

CH2 + R1CHCHCH

CH2

solvent

OH

OH

(220)

≠

δ +

δ −

C

O

PL

Nuδ −

Mδ +

C O + Nu

M

C

− +

O M

ET

.

−

RC

C

O

+ .

Nu

M

(221)

The reactions of allyllithium and allylmagnesium bromide proceed through the ET RC

pathway415,419 with rate-determining ET, while the reactions of allyltin and allyllead proceed via the PL route422,423. 14C KIE in the Zn-promoted Barbier-type reaction of allyl iodide, occurring in solution and not on the metal surface with benzophenone, (equation 222) was found421 to equal 1.041 š 0.006 ( D 0.70 š 0.06), indicating that the binding to carbonyl carbon is changing in the rate-determining TS. This value of 14C