Acylation, Alkylation, and Phosphorylation - American Chemical Society

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Comparative Behavior of Nucleophiles in Gas and Solution Phase: Acylation, Alkylation, and Phosphorylation Marjorie C. Caserio and Jhong K. Kim Department of Chemistry, University of California, Irvine, CA 92717

The present study describes the reactions of neutral alcohols with protonated carboxylic, carbonate, and organophosphorus acids or derivatives generated as gaseous ions under ion cyclotron resonance conditions. Evidence is presented on the mechanisms of these gas-phase ion-molecule reactions, which formally resemble acid-catalyzed acylation and phosphorylation commonly observed in solution. Gas-phase acylation appears to be a displacement process involving acylium ion transfer. Phosphorylation was not observed as such, but ions corresponding to dimethyl metaphosphate reacted rapidly with methanol in an exchange process.

/ \ C Y L A T I O N A N D PHOSPHORYLATION O F NUCLEOPHILES are

among

the

most important and widely studied reactions in chemistry. Formation and hydrolysis of phosphate esters and carboxylic acid derivatives are of great importance in both organic and bioorganic processes and, in fact, are vital to the functioning of living systems. The focus of this paper is on the behavior of neutral nucleophiles, mostly alcohols, with gaseous cations derived from oxyacids of carbon and phosphorus in reactions that resemble, at least superficially, esterification and hydrolysis commonly observed in condensed phase. The objective of studying such reactions in the gas phase is to compare them wherever possible to the corresponding processes in solution; thereby, something is learned about the role of solvent and counterions in moderating the reactions of ions with neutral molecules. Generation of Ions In this study, gaseous organic cations were generated by the technique of ion cyclotron resonance (ICR) spectroscopy, which is a form of mass spectroscopy 0065-2393/87/0215-0065$06.00/0 © 1987 American Chemical Society

Harris and McManus; Nucleophilicity Advances in Chemistry; American Chemical Society: Washington, DC, 1987.

66

NUCLEOPHILICITY

(1-5). Ions are produced by electron impact (from a heated filament) on a neutral sample at low pressure (10~ torr). The ions enter the I C R cell under the influence of external electric and magnetic fields, which constrain them to move in circular orbits with a cyclotron frequency ω that is dependent on the mass (m) and charge (z) of the ion and on the strength of the applied magnetic field H: 7

ω = zH/mc

(1)

The ions are trapped within the cell by applying appropriate voltages to the cell plates: thereby, reactive encounters can occur between ions and neutral molecules: X+ + M —• Y

+

+ Ν

(2)

Both reactant and product ions can be detected in a manner resembling the detection of magnetic nuclei in an N M R experiment. The ions are exposed to a radiofrequency field a) from an external oscillator, and while sweeping the magnetic field H, the ions absorb energy from the applied field when the resonance condition of equation 1 is satisfied (i.e., ω = a> ). The progress of reaction can be monitored as a function of time and ion intensity (Figures 1-3) or as a mass spectrum at a particular time interval (Figure 4-6). The technique is limited to the detection of ions only, and because of the low sample pressures, reactions that are endothermic or have high activation energies are not generally observed. rf

rf

Acylation Proton transfers are among the most rapid of ion-molecule reactions in the gas phase. Depending on the relative proton affinities of thé reactant and product neutrals (M and A in equation 3), an acidic fragment cation com monly transfers a proton to the neutral parent to form M H . +

eV M AH

•AH +

+

primary fragment ions +

+ M —• M H + A

secondary ions

As an example, acetyl derivatives usually fragment under electron impact to produce acetylium ions, C H C O , which, in turn, react with the neutral parent: +

3

CH COX?X C H C O + 3

3

C

H

3

C

Q

X )

[CH COX]H 3

+

+ CH =C=Q 2


(4)

18

6

7

Figure 1. Time plot of ion intensity in the 19-eV ICR spectrum of isopropenyl methyl carbonate at 8 X 10~ torr with Me OH at 1 X 10~ torr. The numbers are m/z values. The horizontal scale represents 200 ms. Only the major ions present are shown.

5. CASERIO A N D KIM

Acylation, Alkylation, and Phosphorylation 67


NUCLEOPHILICITY

6

Figure 2. As in Figure 1 but with CDjOD at 1 X 10~ torr.

68


5. CASERio A N D K I M

Acylation, Alkylation, and Phosphorylation

69

Figure 3. Time plot of the 19-eV ICR spectrum of trimethyl phosphate. The horizontal scale is 200 ms. Only the major ions are shown.

The question of interest is whether the ions produced in this manner behave like their counterparts in solution, which are the conjugate acids of the parent carboxyl derivative. In particular, do they react with added nu cleophiles to transfer the acyl group in a manner related to acid-catalyzed acyl transfer commonly observed in condensed phase? The most prevalent pathway for acyl transfer catalyzed by acids, bases, or enzymes in condensed phase is an addition-elimination sequence involv ing the formation of tetrahedral intermediates, I (Scheme I) (6). A similar

AcXH

I Scheme I. Acyl transfer.


70

NUCLEOPHILICITY

IIMH

HO

(MeO^PO Me#H

155

Ί Γ 110 CD OD 3

M H MD

155 109

Ml

158

TÎ2

Figure 4. ICR mass spectrum of trimethyl phosphate in the presence of Me OH (top) and CD OD (bottom). I8

3



71


M 124 (MeO) Ρ 3

93

14 eV

109 7

6 x 10** torr MH 13 msec

63

94

7

|

125

9

Figure 5. ICR mass spectrum of trimethyl phosphite. process has been found in the gas-phase acylation of anionic nucleophiles (7-9), but the acylation of neutral neucleophiles by gaseous cations appears to take a different pathway (10-14). Thus, in the course of studying the reactions of acetyl derivatives with various nucleophiles under I C R conditions, in no instance have we observed cleavage of the carbonyl C - O bond (10, 11). This finding is surprising because, if a tetrahedral intermediate I is formed, it would be expected to partition among possible routes corresponding to C - O , C - X , and C - N u cleavage in proportion to the relative energies of the products, yet only C - X or C - N u cleavage occurs even when C - O cleavage is energetically favored. Take, for example, the reaction of methanol or methanethiol with protonated thiolacetic acid (Scheme II). The observed product of acyl transfer is II corresponding to loss of H S . If II is formed by way of an addition intermedi ate, then formation of the intermediate by an independent route should give the same product II. However, reaction of the thionic ester III with water failed to give II or any product that could be ascribed to the intervention of a tetrahedral addition intermediate I (15). 2


Harris and McManus; Nucleophilicity Advances in Chemistry; American Chemical Society: Washington, DC, 1987. Μβ·Η

3

(MeO) P

mm 25/100

18

Figure 6. ICR mass spectrum of a mixture of trimethyl phosphite and Me OH at 13 eV. The insets represent the change in the mass spectrum of mlz 109-111 from 15 to 25 ms.

15/100

mk

109

r n O

Z o


73


SH (CH CSH)H*

-H S

MeXH

2

XMe H OH

CH

3

lb

(CH CXMe)H

+

+

3

II

x = o,s

ιH 0 2

S II (CH CXMe)H

+

3

III Scheme II Acylation of sulfide and ether nucleophiles by protonated acyl deriva tives is uncommon in condensed phase; but, in the gas phase, ions of composition A c X M e are readily formed. For example, vinyl and isopropenyl acetates acylate ethers under ICR conditions (11): +

2

-*Ό;

Me'

C s

Η

CH

O'

C s

2

R

CH, +

•C -

-0=C

(5)

R

Me IV

R OC; 2

Me The product ions have the oxonium ion structure IV based on the observation that they acylate the parent neutral and because the alternative dialkoxy structure VI, when generated independently, as in the EI cleavage


74

NUCLEOPHILICITY

of orthoesters or protonation of ketene acetals, does not acylate added nucleophiles: ev

MeC(OMe)

+

i-r

• MeC(OMe) ^

3

CH2=C(OMe)

2

2

VI f^

0

(6)

No product observed On thermodynamic grounds, acylation by way of I is considered unlikely because the addition step is estimated to be endothermic by about 20 kcal/ mol. However, acylation by a displacement pathway involving an acylium ion complex V appears energetically favorable because of energy gained by association of the acylium ion with two nucleophilic "solvent" molecules. The association energy may be as high as 20-40 kcal/mol. This combined with the experimental fact that gaseous acylation preserves the integrity of the acyl C - O bond leads us to conclude that acylation does not occur by an addi tion-elimination sequence but rather by a displacement route involving acylium ion complexes of the type R Y · · · A c · · · X R . +

2

2

Carbonate Esters The chemistry of neutral nucleophiles with protonated carbonate esters differs in interesting ways from that of related carboxylate esters. In the first place, acyl transfer of methoxycarbonyl, M e O C O , to added nucleophiles does not occur (16): +

V

CH,

MeO

R 0 2

CH^

\ -co,

/

C

° = \

Î OMe

R

59 R = Η 73 R = Me R 0-

•

2

Not Observed

OMe


(7)


75


The dominant product ions from mixtures of methanol with methyl vinyl carbonate, methyl isopropenyl carbonate, and methyl tert-butyl carbonate are mlz 59, 73, and 73, respectively. In the case of the vinylic esters, ions mlz 59 and mlz 73 are each formed by two independent routes, decarboxylation and condensation of the protonated ester with methanol. Using deuterium and O-18-labeled methanol, we were able to unravel the reaction pathways involved. To illustrate, Figure 1 shows the change in ion intensity for the reaction of 98% O-18-labeled methanol with isopropenyl acetate. The appearance of mlz 75 means that the oxygen from the alcohol is incorporated in the product ion—the precursor ion being the protonated ester mlz 117. Yet, an abun dance of the unlabeled ion mlz 73 exists that is clearly formed at a faster rate by a pathway that is different from that producing the O-18-labeled ion, mlz 75. The key to both processes is a step involving proton transfer to the vinylic carbon of the ester; mlz 73 arises from dissociation of the C-protonated ester (Scheme III), and mlz 78 arises from the condensation of the C-protonated ester with methanol (Scheme IV).

+

0

CH

II II / \ / \ MeO

\ 0

Ο

Ο

CH

II

/x

Me

MeO

9

I

Ο +

/ \

Me

Ο CH^

II +o

MeO +

Me

^ Ο

Me

Me

m/z 73 Scheme III. Isopropenyl methyl carbonate: pathways to mlz 73.

Support for Schemes III and IV comes from the reaction of isopropenyl acetate with C D O D (Figure 2). The major product ions, besides M H and M D , are mlz 73, 74, 76, and 77, corresponding respectively to decarboxyla tion of M H (mlz 117) and M D (mlz 118) and condensation of C D O D with M H and M D . +

3

+

+

+

3

+

+


76

NUCLEOPHILICITY

Ο

II MeO

Me

Me o= F C +

\ \

Me

ν

II

Me 1

R R 8

rf #H

75

CD OD

76,77

3

Scheme IV. Pathways to mlz 73, 75, 76, and 77.

Moreover, when the C-protonated ester mlz 117 is generated indepen dently by E I cleavage of terf-butyl methyl carbonate in the presence of mlz 73 and 76 are formed, as expected, from independent decar boxylation and condensation reactions (Scheme V). As mentioned, carbonate esters, unlike acetate esters, do not acylate neutral nucleophiles to form ions of the type A c N u . Some additional differences between the ion chemistry of methyl acetate and dimethyl car bonate are noteworthy. Acyl cations R C O are major fragment ions from both

CD3OD,

+

+

Ο

Ο Me

Me

Me

I

-»

Me

0=C

Ο—Ç—Me

\

+

Me

m/zll7

Me

CD3OD Me MeO

Me CD3O

Me m/z 73

Me m/z 76

Scheme V. tert-Butyl methylcarbonate cleavage.




77

esters; but, the acetylium ion (R = Me) from acetates is acidic and rapidly protonates the parent ester whereas the methoxycarbonyl ion (R = MeO) from dimethyl carbonate is a methylating agent that reacts with the parent ester to form M C H (m/z 105): +

3

(MeO) C=0 2

—+ M e O C = 0 mlz 59

M e O C = 0 + ( M e O ) C = 0 -> ( M e O ) mlz 105 2

+

3

(8)

+ C0

2

+

Another methylation product is M e 0 , mlz 61. Formation of mlz 61 is best explained as the result of methyl transfer to the ether oxygen of the parent ester, rather than to the carbonyl oxygen. The ion-molecule complex thus formed may be expected to decarboxylate to give m/z 61 (see also Scheme III): 3

Ο n C.y ^OMfi M e O ^ '~OMe

. (MeO) C=0 MeOÔ=0 • 2

— •

m/z 59

Ο I -f- il 1 ΜβοΟΌΌΜθ L

m/z 105

J

(9) +

Me 0

+

3

^

-CO? Γ Ί I Me 0—MeOC=0

m/z 61

2

XI

To our knowledge, comparable methylation reactions of methyl carbonate esters in condensed phase have not been reported (17, 18). Phosphorylation The two major pathways for phosphorylation reactions in condensed phase are strikingly similar to those for the corresponding acylation reactions (19). One pathway is an addition-elimination process whereby a nucleophile adds to the phosphoryl group to give a pentacoordinate intermediate that col lapses to product by elimination of a nucleophile (mechanism A, Scheme VI). The other pathway is a displacement process in which the phosphoryl group is transferred as tricoordinate metaphosphate to the attacking nucleophile (mechanism B , Scheme VI). Numerous studies have documented the inter vention of metaphosphate in phosphorylation reactions in condensed phase, although metaphosphate has eluded direct detection (19-24). The purpose of the I C R study reported here was to see if gas-phase phosphorylation can be achieved and whether metaphosphate intermediates are involved.


78

NUCLEOPHILICITY

MECHANISM

A

(RO) P=0

+

e

J

R'OH

OH

OR (RO)^P = 0

+

ROH

I OR' MECHANISM

Β

(RO)jP = 0 I OH

+

ROH

\

... ρ Η

/

\

Λ\ RO

Η

Ο

METAPHOSPHATE

RO—Ρ—OH

+

ROH

I OR Scheme VI. Phosphoryl transfer.



79


I C R studies of phosphorus esters have been reported (25-27). However, phosphorylation of neutral nucleophiles is not well documented. Accord ingly, we examined the positive-ion chemistry of alcohols with phosphorus esters. The dominant chemistry of trimethyl phosphate under I C R conditions is the formation of M H (m/z 141) by proton transfer to the parent ester from the fragment ion m/z 110 (Figure 3). In the presence of 98% O-18-labeled methanol, no products were formed that could be ascribed to methanolexchange phosphorylation of the type +

(MeO) P=OH

+

3

+ M e O * H -> ( M e O ) P ( 0 * M e ) = O H

+

2

+ MeOH

However, a minor fragment ion mlz 109 underwent rapid methoxyl exchange as evidenced by the appearance of mlz 111 (from O-18-labeled methanol), and mlz 112 (from C D O D ) after only 15 ms. At longer reaction times, methyl transfer to M gave mlz 155 (from mlz 109 and 111), and mlz 158 (from mlz 112) (Figure 4). These results suggest that mlz 109 is the tricoordinate dimethyl metaphosphate cation VII that reacts according to Schemes VII and VIII. 3

eV

MeO

M

MeOH »•

MeO) P=0 3

e

0 S

+ P=0

MeOH

MeO'

MeO m/z

XII

rrVz 111

109

Scheme VII MeO CDsOD

MeO \

/ MeO

/

7

+ P~0

+

MeOD

CD30

109

112

M

M

+

(MeO)3P —OCDs

(MeO)4P 1W

158 Scheme VIII


80

NUCLEOPHILICITY

On the basis of thermochemical calculations (28, 29) addition of meth anol to dimethyl metaphosphate is likely to be exothermic by at least 26 kcal/ mol, but addition is unlikely to lead to a stable adduct under the lowpressure conditions of the I C R experiment. Indeed, no adduct was ob served, and its formation can only be inferred from the appearance of dissociation products of O M e exchange (Scheme VI).

+

Me

OH

\

//

P+

Me* -

A

H

Λ OMe

Me OMe

MeO

VII

TRMETHYL

109

109

Ρ 1

PHOSPHATE

111 Ο ll p+

26 kcal

Me / ο \

OMe

Η

Me* 111

Scheme VI. Addition of methanol to dimethyl metaphosphate.

So that the methanol exchange reaction of Schemes VII and VIII could be verified, a source of mlz 109 in greater abundance was needed. Attempts to generate mlz 109 by E I cleavage of dimethyl chlorophosphonate, (MeO) P(0)Cl, and dimethyl hydrogen phosphonate, (MeO) P(0)H, were unsuccessful. However, mlz 109 is formed in significant abundance from fragmentation of trimethyl phosphite (equation 10) (Figure 5) (27). 2

2

(MeO) P-OMe — 2

+

(MeO) P =0 mlz 109 2

(10)

Reassuringly, mlz 109 from the phosphite ester behaved in a similar manner to mlz 109 from the phosphate ester. In the presence of O-18-labeled methanol, the fragment ion mlz 109 rapidly produced mlz 111 (Figure 6), and both ions were consumed within 85 ms by subsequent reactions (methyl transfer).


5.

CASERIO A N D K I M

81


That mlz 109 reacts rapidly with methanol whereas the structurally related ion mlz 110 is unreactive (except in proton transfer) may appear to be surprising. However, mlz 110 is a radical cation, and after analysis of the exchange process in terms of single electron shifts according to the method of Pross (30), group coupling to form a bond to phosphorus is favorable only with mlz 109.

If our interpretation of the results is correct, it is amusing to reflect on the contrast between gas-phase and solution-phase phosphorylation. In solu tion, the observables are tetracoordinate orthophosphates with metaphos phate as an inferred intermediate. In the gas phase under I C R conditions, the reverse is true: metaphosphates are the observables, and orthophosphate is the intermediate. Alkylation Certain alcohols, notably tertiary alcohols, are not readily acylated or phosphorylated in the condensed phase under conditions that normally succeed for primary alcohols. Likewise, tertiary alcohols or thiols are not acylated or phosphorylated in the gas phase. Alkylation is the more general reaction. For example, tert-butyl alcohol under I C R conditions condenses with protonated carbonyl and phosphoryl compounds to produce ions of the type X = 0 B u , where X = C or P. The process has been described previously as a displace ment reaction of the type shown in equation 11 (10, 16). +

t

(11) However, tert-butylation of phosphoryl oxygen is notably slower than butylation of carbonyl oxygen.

Literature Cited 1. Beauchamp, J. L. Annu. Rev. Phys. Chem. 1971, 22, 527. 2. Baldeschwieler, J. D. Science (Washington, D.C.) 1968, 159, 263. 3. McIver, R. T., Jr. Rev. Sci. Instrum. 1977, 49, 111.


82

NUCLEOPHILICITY

4. McIver, R. T., Jr. Rev. Sci. Instrum. 1970, 41, 555. 5. Lehman, T. Α.; Bursey, M . M . Ion Cyclotron Resonance Spectrometry; Wiley: New York, 1976. 6. Euranto, Ε. K. In The Chemistry of Carboxylic Acids; Patai, S., Ed., Interscience; New York, 1969; Chapter 11. 7. Nibbering, Ν. M . M . NATO Adv. Study Inst. Ser., Ser. Β 1979, 40, 165. 8. McDonald, R. N . ; Chowdhury, A. K.; Gung, W. Y.; DeWitt, K. D. Abstracts of Papers, 190th National Meeting of the American Chemical Society; Sept. 8-13, Chicago; American Chemical Society: Washington, DC, 1985; ORGN 133 (see also accompanying paper in this volume). 9. Takashima, K.; Riveros, J. M . J. Am. Chem. Soc. 1978, 100, 6128. 10. Kim, J. K.; Caserio, M . C. J. Am. Chem. Soc. 1982, 104, 4624. 11. Kim, J. K.; Caserio, M . C. J. Am. Chem. Soc. 1981, 103, 2124. 12. Tiedemann, P. W.; Riveros, J. M . J. Am. Chem. Soc. 1974, 96, 185. 13. McMahon, T. B. Can. J. Chem. 1978, 56, 670. 14. Beauchamp. J. L. NATO Adv. Study Inst. Ser., Ser. B. 1975, 8, 418. 15. Caserio, M . C.; Kim, J. K. J. Am. Chem. Soc. 1983, 105, 6896. 16. Caserio, M . C.; Kim, J. K. Spectrosc. Int. J. 1983, 2, 207. 17. Shah, Α. Α.; Connors, K. A. J. Pharm. Sci. 1968, 57, 283. 18. Tillett, J. G.; Wiggins, D. E. Tetrahedron Lett. 1971, 911. 19. Westheimer, F. H . Chem. Rev. 1981, 81, 313. 20. Quin, L. D.; Marsi, B. G. J. Am. Chem. Soc. 1985, 107, 3389. 21. Henchman, M . ; Viggiano, Α. Α.; Paulson, J. F. J. Am. Chem. Soc. 1985, 107, 1453. 22. Haake, P.; Allen, G. W. Bioorg. Chem. 1980, 9, 325. 23. Skoog, M . T.; Jencks, W. P. J. Am. Chem. Soc. 1983, 105, 3356. 24. Rebek, J., Jr.; Gavina, F.; Navarro, C. J. Am. Chem. Soc. 1978, 100, 8113. 25. Ausbiojo, Ο. I.; Braumann, J. I. J. Am. Chem. Soc. 1977, 99, 7707. 26. Hodges, R. V.; Sullivan, S. Α.; Beauchamp, J. L. J. Am. Chem. Soc. 1980, 102, 935. 27. Hodges, R. V.; McDonnell, T. J.; Beauchamp, J. L..J.Am. Chem. Soc. 1980, 102, 1327. 28. Guthrie, J. P. J. Am. Chem. Soc. 1978, 100, 5892. 29. Guthrie, J. P. J. Am. Chem. Soc. 1977, 99, 3991. 30. Pross, A. Acc. Chem. Res. 1985, 18, 212. RECEIVED

for review November 6, 1985.

ACCEPTED

February 28, 1986.


Acylation, Alkylation, and Phosphorylation - American Chemical Society

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